Organic compounds

ABSTRACT

The invention relates to particular substituted deuterated heterocycle fused gamma-carbolines, their prodrugs, in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving 5-HT2A receptor, serotonin transporter (SERT) and/or pathways involving dopamine D1/D2 receptor signaling systems, and/or the treatment of residual symptoms.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a United States Application under 35 U.S.C. § 371claiming priority to and the benefit of PCT Application No.PCT/US2017/024137, filed on Mar. 24, 2017, which claims priority to andthe benefit of U.S. Provisional Patent Application Ser. No. 62/313,629,filed on Mar. 25, 2016, the contents of each of which are hereinincorporated by reference in their entireties.

FIELD OF THE INVENTION

The invention relates to particular deuterated heterocycle fusedgamma-carbolines, in free, pharmaceutically acceptable salt and/orsubstantially pure form as described herein, pharmaceutical compositionsthereof, and methods of use in the treatment of diseases involving5-HT_(2A) receptor, serotonin transporter (SERT) and/or pathwaysinvolving dopamine D₁/D₂ receptor signaling systems, e.g., diseases ordisorders such as anxiety, psychosis, schizophrenia, sleep disorders,sexual disorders, migraine, conditions associated with cephalic pain,social phobias, gastrointestinal disorders such as dysfunction of thegastrointestinal tract motility and obesity; depression and mooddisorders associated with psychosis or Parkinson's disease; psychosissuch as schizophrenia associated with depression; bipolar disorder; andother psychiatric and neurological conditions, as well as tocombinations with other agents.

BACKGROUND OF THE INVENTION

Psychosis, particularly schizophrenia and schizoaffective disorder,affects an estimated 1-2% of the population worldwide. Schizophrenia iscomprised of three phases: prodromal phase, active phase and residualphase. Prodromal phase is an early phase wherein subclinical signs andsymptoms are observed. These symptoms may include loss of interest inusual pursuits, withdrawal from friends and family members, confusion,trouble with concentration, feeling of listlessness and apathy. Activephase is characterized by exacerbations of positive symptoms such asdelusions, hallucinations and suspiciousness. Residual phase ischaracterized by negative symptoms such as emotional withdrawal, passivesocial withdrawal, and stereotyped thinking; and generalpsychopathological symptoms including active social avoidance, anxiety,tension, and somatic concerns. Residual phase symptoms also are oftenaccompanied by depression, cognitive dysfunction and insomnia.Collectively, these residual phase symptoms are not well-treated by manyantipsychotic drugs currently available on the market and therefore areusually observed after the active phase symptoms have subsided aftertreatment. This phase of the illness is when patients would like toreturn to more productive and fulfilling lives, but since the residualnegative symptoms and cognitive impairment are not properly treated, itfrustrates the return to such a function. There remains an urgent needfor anti-psychotic agent, which can treat not just the active or acutephase symptoms, but also the residual phase symptoms of psychosis, e.g.,schizophrenia. In addition, there is a need for medications to treatthese symptoms that are free from undesirable side effects caused byoff-target interactions with histamine H1 and muscarinic acetylcholinereceptor systems.

Substituted heterocycle fused gamma-carbolines are known to be agonistsor antagonists of 5-HT2 receptors, particularly 5-HT_(2A) receptors, intreating central nervous system disorders. These compounds have beendisclosed in U.S. Pat. No. 6,548,493; 7,238,690; 6,552,017; 6,713,471;7,183,282; U.S. RE39680, and U.S. RE39679, as novel compounds useful forthe treatment of disorders associated with 5-HT_(2A) receptor modulationsuch as obesity, anxiety, depression, psychosis, schizophrenia, sleepdisorders, sexual disorders migraine, conditions associated withcephalic pain, social phobias, gastrointestinal disorders such asdysfunction of the gastrointestinal tract motility, and obesity.

PCT/US08/03340 (WO 2008/112280) and U.S. application Ser. No. 10/786,935disclose methods of making substituted heterocycle fusedgamma-carbolines and uses of these gamma-carbolines as serotoninagonists and antagonists useful for the control and prevention ofcentral nervous system disorders such as addictive behavior and sleepdisorders.

WO/2009/145900 discloses use of particular substituted heterocycle fusedgamma-carbolines for the treatment of a combination of psychosis anddepressive disorders as well as sleep, depressive and/or mood disordersin patients with psychosis or Parkinson's disease. In addition todisorders associated with psychosis and/or depression, this patentapplication discloses and claims use of these compounds at a low dose toselectively antagonize 5-HT_(2A) receptors without affecting orminimally affecting dopamine D₂ receptors, thereby useful for thetreatment of sleep disorders without the side effects of the dopamine D₂pathways or side effects of other pathways (e.g., GABA_(A) receptors)associated with conventional sedative-hypnotic agents (e.g.,benzodiazepines) including but not limited to the development of drugdependency, muscle hypotonia, weakness, headache, blurred vision,vertigo, nausea, vomiting, epigastric distress, diarrhea, joint pains,and chest pains.

Furthermore, it has been discovered that these particular substitutedheterocycle fused gamma-carboline compounds (the compounds describedherein below) are effective in treating not just acute symptoms, butalso residual symptoms of psychosis. Therefore, the invention providesmethods of using the particular substituted heterocycle fusedgamma-carboline compounds (the compounds described herein below), eitheralone or as an adjunctive therapy for the treatment of residual symptomsof psychosis, particularly schizophrenia.

WO 2009/114181 discloses methods of preparing toluenesulfonic acidaddition salt crystals of particular substituted heterocycle fusedgamma-carbolines, e.g., toluenesulfonic acid addition salt of4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′, 4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone.

WO 2011/133224 discloses prodrugs/metabolites of substituted heterocyclefused gamma-carboline for improved formulation, e.g.,extended/controlled release formulation. This application discloses thatheterocycle fused gamma-carboline N-substituted with a4-fluorophenyl(4-hydroxy)butyl moiety are shown to have high selectivityfor the serotonin transporter (SERT) relative to the heterocycle fusedgamma-carboline containing 4-fluorophenylbutanone. The hydroxy group onthese compounds, however, is inter-converted to and from the ketonewithin the plasma and the brain, allowing it to serve as a reservoir forthe 4-fluorophenylbutanone drug. While substituted heterocycle fusedgamma-carbolines and their uses are known, our inventors havesurprisingly found that particular substituted heterocycle fusedgamma-carbolines, while less active in in-vitro tests, areinter-converted between these less active compounds and the highlyactive ketone drug within the plasma and the brain. Our inventors havefurther provided prodrugs of particular substituted heterocycle fusedgamma-carbolines that have altered pharmacokinetic profile, e.g.,altered mechanisms and/or rate of absorption and distribution, andtherefore may be useful for an improved formulation and/or forcontrolling the duration of the effect of the drug in the body (e.g.,for sustained- or controlled release).

WO 2013/155505 discloses compounds which block the in vivointer-conversion between the hydroxy and the ketone, by incorporating analkyl substituent on the carbon bearing the hydroxyl group, thusyielding compounds which antagonize 5-HT_(2A) receptors and also inhibitserotonin re-uptake transporter.

The major routes of metabolism of the compounds previously disclosed areN-demethylation catalyzed by CYP 3A4, and ketone reduction catalyzed byketone reductase. N-dealkylation by cytochrome oxidase enzymes is knownto occur via an initial oxidation of one or more of the carbon atomsalpha to the nitrogen atom. The family of enzymes that catalyze ketonereduction is large and varied, and the mechanism has not been absolutelyelucidated. It is of interest that, mechanistically, ketone reductionmay operate either by way of the enol tautomer of the ketone or the ketotautomer.

WO 2015/154025 discloses generic deuterated heterocycle fused gammacarbolines for the purpose of reducing metabolic degradation bypartially limiting metabolism of the ketone and/or the N-methylsubstituent.

SUMMARY OF THE INVENTION

Applicants have unexpectedly discovered that the major routes ofmetabolism of fused heterocycle gamma carboline of Formula Q are by wayof N-dealkylation and alpha-oxidation at the piperazine ring, and byreduction of the carbonyl, to yield the compounds of Formula Q-1, Q-2and Q-3, as shown below:

Applicants have further found that the alcohol metabolite of Formula Q-2retains significant pharmacological activity.

Without being bound by theory, the current invention provides compoundswhich specifically limit and/or prevent metabolism occurring by thesepathways. Due to the very similar properties of deuterium (²H) atomscompared to normal hydrogen atoms (¹H), drug compounds in whichdeuterium is substituted for hydrogen are believed to generally havesimilar biological activity to the non-deuterated analog, butpotentially with improved pharmacokinetic properties. The extent towhich such a substitution will result in an improvement ofpharmacokinetic properties without a too severe loss in pharmacologicactivity is variable. Thus, in some circumstances, the resultingdeuterated compound only a moderate increase in pharmacokineticstability, while in other circumstances, the resulting deuteratedcompound may have significantly improved stability. Moreover, it may bedifficult to predict with certainty the effects of simultaneousdeuterium substitutions. These may or may not result in additive(synergistic) improvement in metabolic stability.

The current invention provides compounds containing a trideuteratedN-methyl, and/or a di-deuterated methylene adjacent to the N-methyl.These novel compounds antagonize 5-HT_(2A) receptors, inhibit theserotonin re-uptake transporter, and modulate dopaminergic proteinphosphorylation, in a like manner as to their natural hydrogen analogs.However, these compounds display an unexpectedly improved metabolicstability.

In the first embodiment, the invention provides a compound of Formula I:

in free or salt form, e.g., in pharmaceutically acceptable salt form(e.g., tosylate).

In the second embodiment, the invention provides a compound of FormulaII:

in free or salt form, e.g., in pharmaceutically acceptable salt form(e.g., tosylate).

In the third embodiment, the invention provides a compound of formulaIII:

in free or salt form, e.g., in pharmaceutically acceptable salt form(e.g., tosylate).

In the fourth embodiment, the invention provides a compound of formulaIV, in

wherein:

R¹ is CH₃ or CD₃;

R² and R³ are either both H or both D;

provided that when R¹ is CH₃ R² and R³ are both D;

free or salt form, e.g., in pharmaceutically acceptable salt form (e.g.,tosylate).

In additional embodiments, the invention provides compounds as follows:

-   -   1.1 A compound of any of Formulas I to IV, wherein the compound        is in free or pharmaceutically acceptable salt form;    -   1.2 A compound of Formula 1.1, wherein the salt form is an acid        addition salt of a pharmaceutically acceptable acid;    -   1.3 A compound of Formula 1.2 wherein the acid is        toluenesulfonic acid;    -   1.4 A compound of any of Formulas I to IV or 1.1-1.3, wherein        the Compound is in substantially pure diastereomeric form (i.e.,        substantially free from other diastereomers);    -   1.5 A compound of any of Formulas I to IV or 1.1-1.4, wherein        the Compound has a diastereomeric excess of greater than 70%,        preferably greater than 80%, more preferably greater than 90%        and most preferably greater than 95%;    -   1.6 A compound of any of Formulas I to IV or 1.1-1.5, wherein        the compound has greater than natural incorporation of deuterium        at the indicated deuterium positions of the structure (i.e.,        greater than 0.0156%);    -   1.7 A compound of any of Formulas I to IV or 1.1-1.6, wherein        the compound has substantially greater than natural        incorporation of deuterium at the indicated deuterium positions        of the structure (e.g., greater than 0.1%, or greater than 0.5%,        or greater than 1%, or greater than 5%);    -   1.8 A compound of any of Formulas I to IV or 1.1-1.7, wherein        the compound has greater than 50% incorporation of deuterium at        the indicated deuterated positions of the structure (i.e.,        greater than 50 atom % D), e.g., greater than 60%, or greater        than 70%, or greater than 80%, or greater than 90% or greater        than 95%, or greater than 96%, or greater than 97%, or greater        than 98%, or greater than 99%.

In a second aspect, the invention provides a pharmaceutical compositioncomprising the compound of any of Formulas I to IV or 1.1-1.8 (theCompounds of the Invention), in free or pharmaceutically acceptable saltform, in admixture with a pharmaceutically acceptable diluent orcarrier, e.g. to provide immediate release or to provide sustained ordelayed release.

In a further embodiment of the second aspect, the PharmaceuticalComposition of the Invention is for a sustained or delayed release,e.g., a depot formulation. In one embodiment, the depot formulationcomprises the Compounds of the Invention in a polymeric matrix. Inanother embodiment, the Compounds of the Invention are dispersed ordissolved within the polymeric matrix. In a further embodiment, thepolymeric matrix comprises standard polymers used in depot formulationssuch as polymers selected from a polyester of a hydroxy fatty acid andderivatives thereof, or a polymer of an alkyl alpha-cyanoacrylate, apolyalkylene oxalate, a poly(ortho ester), a polycarbonate, apolyortho-carbonate, a poly(amino acid), a hyaluronic acid ester, andmixtures thereof. In a further embodiment, the polymer is selected froma group consisting of polylactide, poly d,l-lactide, poly glycolide,PLGA 50:50, PLGA 75:25, PLGA 85:15 and PLGA 90:10 polymer. In anotherembodiment, the polymer is selected from poly(glycolic acid),poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the foregoing,poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone,polydioxonone, poly(ortho carbonates), poly(acetals), poly(lacticacid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone),polyanhydrides, and natural polymers including albumin, casein, andwaxes, such as, glycerol mono- and distearate, and the like. In aparticular embodiment, the polymeric matrix comprises poly(d,l-lactide-co-glycolide). Any of the Compositions hereinbeforedescribed may be a pharmaceutical composition wherein said compositionis in admixture with a pharmaceutically acceptable diluent or carrier.

The (Pharmaceutical) depot formulations as hereinbefore described areparticularly useful for sustained or delayed release, wherein theCompounds of the Invention are released upon degradation of thepolymeric matrix. These Compositions may be formulated for controlled-and/or sustained-release of the Compounds of the Invention (e.g., as adepot composition) over a period of up to 180 days, e.g., from about 14to about 30 to about 180 days. For example, the polymeric matrix maydegrade and release the Compounds of the Invention over a period ofabout 30, about 60 or about 90 days. In another example, the polymericmatrix may degrade and release the Compounds of the Invention over aperiod of about 120, or about 180 days.

In still another further embodiment, the Pharmaceutical Compositions ofthe Invention, particularly the depot compositions of the Invention, areformulated for administration by injection.

In a third aspect, the invention provides the Compounds of the Inventionas hereinbefore described in an oral sustained or delayed releaseformulation. For example, the invention provides an osmotic controlledrelease oral delivery system (OROS) for delivery of the Compounds of theInvention, e.g. analogous to the systems described in WO 2000/35419 andEP 1 539 115 (U.S. Pub. No. 2009/0202631), the contents of each of whichapplications are incorporated by reference in their entirety. Thereforein one embodiment of this aspect, the invention provides apharmaceutical composition or device comprising (a) a gelatin capsulecontaining a Compound of the Invention in free or pharmaceuticallyacceptable salt form or a Pharmaceutical Composition of the Invention,as hereinbefore described; (b) a multilayer wall superposed on thegelatin capsule comprising, in outward order from the capsule: (i) abarrier layer, (ii) an expandable layer, and (iii) a semipermeablelayer; and (c) and orifice formed or formable through the wall.(Composition P.1)

In another embodiment of this aspect, the invention provides acomposition comprising a gelatin capsule containing a liquid, theCompounds of the Invention in free or pharmaceutically acceptable saltform or a Pharmaceutical Composition of the Invention as hereinbeforedescribed, the gelatin capsule being surrounded by a composite wallcomprising a barrier layer contacting the external surface of thegelatin capsule, an expandable layer contacting the barrier layer, asemi-permeable layer encompassing the expandable layer, and an exitorifice formed or formable in the wall. (Composition P.2)

In still another embodiment of the third aspect, the invention providesa composition comprising a gelatin capsule containing a liquid, theCompound of the Invention in free or pharmaceutically acceptable saltform or a Pharmaceutical Composition of the Invention as hereinbeforedescribed, the gelatin capsule being surrounded by a composite wallcomprising a barrier layer contacting the external surface of thegelatin capsule, an expandable layer contacting the barrier layer, asemipermeable layer encompassing the expandable layer, and an exitorifice formed or formable in the wall, wherein the barrier layer formsa seal between the expandable layer and the environment at the exitorifice. (Composition P.3)

In still another embodiment of the third aspect, the invention providesa composition comprising a gelatin capsule containing a liquid, theCompound of the Invention in free or pharmaceutically acceptable saltform or a Pharmaceutical Composition of the Invention as hereinbeforedescribed, the gelatin capsule being surrounded by a barrier layercontacting the external surface of the gelatin capsule, an expandablelayer contacting a portion of the barrier layer, a semi-permeable layerencompassing at least the expandable layer, and an exit orifice formedor formable in the dosage form extending from the external surface ofthe gelatin capsule to the environment of use. (Composition P.4). Theexpandable layer may be formed in one or more discrete sections, such asfor example, two sections located on opposing sides or ends of thegelatin capsule.

In a particular embodiment of the third aspect, the Compound of theInventions in the Osmotic-controlled Release Oral delivery System (i.e.,in Composition P.1-P.4) are in a liquid formulation, which formulationmay be neat, liquid active agent, liquid active agent in a solution,suspension, emulsion or self-emulsifying composition or the like.

Further information on Osmotic-controlled Release Oral delivery Systemcomposition including characteristics of the gelatin capsule, barrierlayer, an expandable layer, a semi-permeable layer; and orifice may befound in WO 2000/35419, the contents of which are incorporated byreference in their entirety. Other Osmotic-controlled Release Oraldelivery System for the Compound or the Pharmaceutical Composition ofthe Invention may be found in EP 1 539 115 (U.S. Pub. No. 2009/0202631),the contents of which are incorporated by reference in their entirety.

Therefore, in another embodiment of the third aspect, the inventionprovides a composition or device comprising (a) two or more layers, saidtwo or more layers comprising a first layer and a second layer, saidfirst layer comprises the Compound of the Invention, in free orpharmaceutically acceptable salt form, or a Pharmaceutical Compositionas herein before described said second layer comprises a polymer; (b) anouter wall surrounding said two or more layers; and (c) an orifice insaid outer wall. (Composition P.5)

Composition P.5 preferably utilizes a semi-permeable membranesurrounding a three-layer-core: in these embodiments the first layer isreferred to as a first drug layer and contains low amounts of drug(e.g., the Compounds of the Invention) and an osmotic agent such assalt, the middle layer referred to as the second drug layer containshigher amounts of drug, excipients and no salt; and the third layerreferred to as the push layer contains osmotic agents and no drug. Atleast one orifice is drilled through the membrane on the first druglayer end of the capsule-shaped tablet. (Composition P.6)

Composition P.5 or P.6 may comprise a membrane defining a compartment,the membrane surrounding an inner protective subcoat, at least one exitorifice formed or formable therein and at least a portion of themembrane being semi-permeable; an expandable layer located within thecompartment remote from the exit orifice and in fluid communication withthe semi-permeable portion of the membrane; a first drug layer locatedadjacent the exit orifice; and a second drug layer located within thecompartment between the first drug layer and the expandable layer, thedrug layers comprising the Compound of the Invention in free orpharmaceutically acceptable salt thereof. Depending upon the relativeviscosity of the first drug layer and second drug layer, differentrelease profiles are obtained. It is imperative to identify the optimumviscosity for each layer. In the present invention, viscosity ismodulated by addition of salt, sodium chloride. The delivery profilefrom the core is dependent on the weight, formulation and thickness ofeach of the drug layers.

In a particular embodiment, the invention provides Composition P.7,wherein the first drug layer comprising salt and the second drug layercontaining no salt. Composition P.5-P.7 may optionally comprise aflow-promoting layer between the membrane and the drug layers.Compositions P.1-P.7 will generally be referred to as Osmotic-controlledRelease Oral delivery System Composition.

In a fourth aspect, the invention provides a method (Method I) for thetreatment or prophylaxis of a central nervous system disorder,comprising administering to a patient in need thereof, a compound ofFormulas I to IV or 1.1-1.8, in free or pharmaceutically acceptable saltform, or a pharmaceutical composition as hereinbefore described, andoptionally wherein the compound of Formulas I to IV or 1.1-1.8 isadministered in an effective dose which is lower than the effective dosefor treatment of the same disorder using the compound of Formula Q.

In a further embodiment of the fourth aspect, the invention providesMethod I wherein the method is further as described in the followingformulae:

-   -   7.1 Method I, wherein the central nervous system disorder is one        or more disorders associated with dementia, e.g., disorders        associated with mild cognition impairment and dementing        illnesses including senile dementia, Alzheimer's disease, Pick's        disease, fronto-temporal dementia, parasupranuclear palsy,        dementia with Lewy bodies, vascular dementia, Huntington's        disease, Parkinson's disease, multiple sclerosis, amyotrophic        lateral sclerosis, Down syndrome, elderly depression,        Wernicke-Korsakoffs syndrome, cortico-basal degenerations and        prion disease, autism and attention deficit hyperactivity        disorder;    -   7.2 Method I or 7.1, wherein the disorders associated with        dementia is selected from the group consisting of (1) behavioral        or mood disorders such as agitation/irritation,        aggressive/assaultive behavior, anger, physical or emotional        outbursts; (2) psychosis; (3) depression; and (4) sleep        disorders;    -   7.3 Method I or 7.1, wherein the central nervous system disorder        is agitation/irritation, aggressive/assaultive behavior, anger,        physical or emotional outbursts;    -   7.4 Method I, wherein the central nervous system disorder is a        disorder selected from a group consisting of obesity, anxiety,        depression (for example refractory depression and Major        Depressive Disorder (MDD)), psychosis, schizophrenia, sleep        disorders (particularly sleep disorders associated with        schizophrenia and other psychiatric and neurological diseases),        sexual disorders, migraine, conditions associated with cephalic        pain, social phobias, agitation in dementia (e.g., agitation in        Alzheimer's disease), agitation in autism and related autistic        disorders, and gastrointestinal disorders such as dysfunction of        the gastrointestinal tract motility;    -   7.5 Method I or any of 7.2-7.4, wherein the central nervous        system disorder is a disorder involving serotonin 5-HT_(2A),        dopamine D₁/D₂ receptor system and/or serotonin reuptake        transporter (SERT) pathways as similarly described in        WO/2009/145900, the contents of which are herein incorporated by        reference in their entirety;    -   7.6 Method I or any of Formulae 7.2-7.5, wherein the central        nervous system disorder is a disorder involving serotonin        reuptake transporter (SERT) pathways;    -   7.7 Method I or any of Formulae 7.2-7.6, wherein the central        nervous system disorder is a disorder selected from the        following: (i) psychosis, e.g., schizophrenia, in a patient        suffering from depression; (2) depression in a patient suffering        from psychosis, e.g., schizophrenia; (3) mood disorders        associated with psychosis, e.g., schizophrenia or Parkinson's        disease; and (4) sleep disorders associated with psychosis,        e.g., schizophrenia or Parkinson's disease; (5) depression; (6)        anxiety; (7) post-traumatic stress disorder; or (8) impulse        control disorder, e.g., intermittent explosive disorder;    -   7.8 Method I or any of Formulae 7.2-7.7, wherein the central        nervous system disorder is psychosis, e.g., schizophrenia and        said patient is a patient suffering from depression;    -   7.9 Method I or any of Formulae 7.2-7.8, wherein said patient is        unable to tolerate the side effects of convention antipsychotic        drugs, e.g., chlorpromazine, haloperidol, droperidol,        fluphenazine, loxapine, mesoridazine, molindone, perphenazine,        pimozide, prochlorperazine, promazine, thioridazine,        thiothixene, trifluoperazine, clozapine, aripiprazole,        olanzapine, quetiapine, risperidone and ziprasidone;    -   7.10 Method I or any of Formulae 7.2-7.9, wherein said patient        is unable to tolerate the side effects of convention        antipsychotic drugs, e.g., haloperidol, aripiprazole, clozapine,        olanzapine, quetiapine, risperidone, and ziprasidone;    -   7.11 Method I or any of Formulae 7.2-7.10, wherein said disorder        is depression and said patient is a patient suffering from        psychosis, e.g., schizophrenia, or Parkinson's disease;    -   7.12 Method I or any of Formulae 7.2-7.6, wherein said disorder        is sleep disorder and said patient is suffering from depression;    -   7.13 Method I or any of 7.2-7.6, wherein said one or more        disorders is sleep disorder and said patient is suffering from        psychosis, e.g., schizophrenia;    -   7.14 Method I or any of 7.2-7.6, wherein said one or more        disorders is sleep disorder and said patient is suffering from        Parkinson's disease;    -   7.15 Method I or any of 7.2-7.6, wherein said one or more        disorders is sleep disorder and said patient is suffering from        depression and psychosis, e.g., schizophrenia, or Parkinson's        disease;    -   7.16 Method I or any of 7.1-7.6, wherein the central nervous        system disorder is residual symptoms of psychosis, for example,        schizophrenia (e.g., residual sub-type), delusional disorder        (e.g., somatic type), major depression with psychosis, bipolar        disorder with psychotic symptoms, brief psychotic disorder,        schizophreniform disorder, schizoaffective disorder or psychosis        caused by a medical condition or substance use. Preferably, the        patient is suffering from residual symptoms of schizophrenia;    -   7.17 Method I or any of 7.1-7.6, wherein the residual phase        symptoms include: negative symptoms such as blunted affect,        emotional withdrawal, poor rapport, passive or apathetic social        withdrawal, difficulty in abstract thinking, lack of spontaneity        and flow of conversation and stereotyped thinking; general        psychopathology symptoms such as somatic concern, anxiety, guilt        feelings, tension, mannerisms and posturing, depression, motor        retardation, uncooperativeness, unusual thought content,        disorientation, poor attention, lack of judgment and insight,        disturbance of volition, poor impulse control, preoccupation and        active social avoidance; cognitive impairment and sleep        disorders (e.g., insomnia);    -   7.18 Any of the foregoing methods, wherein the effective amount        is 1 mg-1000 mg, preferably 2.5 mg-50 mg, still preferably 1-40        mg, e.g., 1-10 mg, e.g., 10 mg, 20 mg, or greater than 20 mg,        e.g., 30 mg, 40 mg;    -   7.19 Any of the foregoing methods, wherein the effective amount        is 1 mg-100 mg per day, preferably 2.5 mg-50 mg per day, still        preferably 1-40 mg/day, e.g., 1-10 mg/day, e.g., 10 mg/day, 20        mg/day, or greater than 20 mg/day, e.g., 30 mg/day, 40 mg/day;    -   7.20 Any of the foregoing methods wherein a condition to be        treated is dyskinesia, e.g. in a patient receiving dopaminergic        medications, e.g., medications selected from levodopa and        levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B        inhibitors), dopamine agonists, e.g., levodopa, and        anticholinergics;    -   7.21 Any of the foregoing methods wherein the patient suffers        from Parkinson's disease;    -   7.22 Any of the foregoing methods wherein the patient does not        respond to a selective serotonin re-uptake inhibitor, e.g.        selected from one or more of citalopram (Celexa, Cipramil,        Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox,        Cital); dapoxetine (Priligy); escitalopram (Lexapro, Cipralex,        Seroplex, Esertia); fluoxetine (Depex, Prozac, Fontex, Seromex,        Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin (EUR), Fluox        (NZ), Depress (UZB), Lovan (AUS), Prodep (IND)); fluvoxamine        (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox); indalpine        (Upstene); paroxetine (Paxil, Seroxat, Sereupin, Aropax,        Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine,        Deparoc); sertraline (Zoloft, Lustral, Serlain, Asentra);        vilazodone (Viibryd); or zimelidine (Zelmid, Normud);    -   7.23 Any of the foregoing methods wherein the patients is also        receiving a selective serotonin re-uptake inhibitor, e.g.        selected from one or more of citalopram (Celexa, Cipramil,        Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox,        Cital); dapoxetine (Priligy); escitalopram (Lexapro, Cipralex,        Seroplex, Esertia); fluoxetine (Depex, Prozac, Fontex, Seromex,        Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin (EUR), Fluox        (NZ), Depress (UZB), Lovan (AUS), Prodep (IND)); fluvoxamine        (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox); indalpine        (Upstene); paroxetine (Paxil, Seroxat, Sereupin, Aropax,        Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine,        Deparoc); sertraline (Zoloft, Lustral, Serlain, Asentra);        vilazodone (Viibryd); or zimelidine (Zelmid, Normud);    -   7.24 Any of the foregoing methods wherein the patients is        suffering from autistic spectrum disorder, e.g., autism or        Asperger Syndrome;    -   7.25 Any of the foregoing methods wherein the patients is        suffering from dementia, e.g., disorders associated with mild        cognition impairment and dementing illnesses including senile        dementia, Alzheimer's disease, Pick's disease, fronto-temporal        dementia, parasupranuclear palsy, dementia with Lewy bodies,        vascular dementia, Huntington's disease, Parkinson's disease,        multiple sclerosis, amyotrophic lateral sclerosis, Down        syndrome, elderly depression, Wernicke-Korsakoff s syndrome,        cortico-basal degenerations and prion disease, autism and        attention deficit hyperactivity disorder;    -   7.26 Any of the foregoing methods wherein the patient is also        receiving a cholinesterase inhibitor (e.g., acetylcholinesterase        inhibitor) or an N-Methyl D-Aspartate (NMDA) receptor        antagonist, in free or pharmaceutically acceptable salt form;    -   7.27 Method 7.26, wherein the cholinesterase inhibitor (e.g.,        acetylcholinesterase inhibitor) is selected from the group        consisting of Tacrine, rivastigmine (Exelon), donepezil        (Aricept), and galantamine (Razadyne, formerly called Reminyl))        in free or pharmaceutically acceptable salt form;    -   7.28 Method 7.26, wherein the cholinesterase inhibitor (e.g.,        acetylcholinesterase inhibitor) is donepezil in free or        pharmaceutically acceptable salt form;    -   7.29 Method 7.26, wherein the NMDA receptor antagonist is        memantine in free or pharmaceutically acceptable salt form;    -   7.30 Any of the foregoing methods further comprising        administering one or more other therapeutic agents such as        additional antipsychotic agents and/or anti-depressive agents        and/or hypnotic agents;    -   7.31 Method 7.30, wherein the one or more other therapeutic        agents are selected from anti-depressive agents such as        compounds that modulate GABA activity (e.g., enhances the        activity and facilitates GABA transmission), a GABA-B agonist, a        5-HT modulator (e.g., a 5-HT₁A agonist, a 5-HT_(2A) antagonist,        a 5-HT2A inverse agonist, etc.), a melatonin agonist, an ion        channel modulator (e.g., blocker), a serotonin-2        antagonist/reuptake inhibitor (SARIs), an orexin receptor        antagonist, an H3 agonist, a noradrenergic antagonist, a galanin        agonist, a CRH antagonist, human growth hormone, a growth        hormone agonist, estrogen, an estrogen agonist, a neurokinin-1        drug; and antipsychotic agents, e.g., atypical antipsychotic        agents, in free or pharmaceutically acceptable salt form;    -   7.32 Method 7.30 or 7.31, wherein the one or more other        therapeutic agents are antipsychotic agents, e.g.,        chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine,        mesoridazine, molindone, perphenazine, pimozide,        prochlorperazine promazine, thioridazine, thiothixene,        trifluoperazine, clozapine, aripiprazole, olanzapine,        quetiapine, risperidone, ziprasidone, paliperidone, asenapine,        lurasidone, iloperidone, cariprazine, amisulpride, zotepine,        sertindole, wherein the one or more other therapeutic agents are        administered as an adjunct to the compound of Formulas I to IV        or 1.1-1.8 or the compound of Formulas I to IV or 1.1-1.8 is an        adjunct to the one or more other therapeutic agents.

In a particular embodiment of the fourth aspect, the invention providesa method (Method I_(P)) for the treatment or prophylaxis of a centralnervous system disorder as hereinbefore described, comprisingadministering to a patient in need thereof:

-   -   7.4P a compound of Formulas I to IV or 1.1-1.8, in free or        pharmaceutically acceptable salt form;    -   7.8P a Pharmaceutical or Depot Composition as hereinbefore        described; or    -   7.11P Osmotic-controlled Release Oral delivery System        Composition as hereinbefore described.

In a further embodiment of the fourth aspect, the invention providesMethod I_(P), wherein the method is further described in any one offormulae 7.1-7.32.

In a particular embodiment of the fourth aspect, the invention providesMethod I, I_(P), or any of 7.1-7.32, wherein the disorder isschizophrenia or sleep disorder.

In a particular embodiment of the fourth aspect, the invention providesMethod I, I_(P), or any of 7.1-7.32, wherein the disorder is depressionor anxiety.

In a particular embodiment of the fourth aspect, the invention providesMethod I, I_(P), or any of 7.1-7.32, wherein the disorder ispost-traumatic stress disorder or an impulse control disorder, e.g.,intermittent explosive disorder.

In a particular embodiment of the fourth aspect, the invention providesMethod I, I_(P), or any of 7.1-7.32, wherein the disorder ispost-traumatic stress disorder or an impulse control disorder, e.g.,intermittent explosive disorder in a patient suffering from dementia,e.g., senile dementia, Alzheimer's disease, Pick's disease,fronto-temporal dementia, parasupranuclear palsy, dementia with Lewybodies, vascular dementia, Huntington's disease, Parkinson's disease,multiple sclerosis, amyotrophic lateral sclerosis, Down syndrome,elderly depression, Wernicke-Korsakoffs syndrome, cortico-basaldegenerations, prion disease, autism and/or attention deficithyperactivity disorder.

In still another embodiment of the fourth aspect, the invention providesMethod I, I_(P), or any of 7.1-7.32, wherein the Depot Composition ofthe Invention is administered for controlled- and/or sustained-releaseof the Compounds of the Invention over a period of from about 14 days,about 30 to about 180 days, preferably over the period of about 30,about 60 or about 90 days. Controlled- and/or sustained-release isparticularly useful for circumventing premature discontinuation oftherapy, particularly for antipsychotic drug therapy wherenon-compliance or non-adherence to medication regimes is a commonoccurrence.

In a fifth aspect, the invention provides a method (Method II) for theprophylaxis or treatment one or more sleep disorders, agitation,aggressive behaviors, post-traumatic stress disorder and/or impulsecontrol disorder, e.g., intermittent explosive disorder, comprisingadministering to a patient in need thereof a compound as described inthe following formulae:

-   -   8.1 a compound of Formulas I to IV or 1.1-1.8, in free or        pharmaceutically acceptable salt form;    -   8.2 a Pharmaceutical or Depot Composition as hereinbefore        described;    -   8.3 Osmotic-controlled Release Oral delivery System Composition        as hereinbefore described.

In one embodiment of the fifth aspect, the invention provides Method IIor any of 8.1-8.3, wherein the disorder is sleep disorders. In anotherembodiment of the fifth aspect, the invention provides Method II,wherein the disorder is agitation, aggressive behaviors, post-traumaticstress disorder and/or impulse control disorder, e.g., intermittentexplosive disorder.

In a further embodiment of the fifth aspect, the invention providesMethod II, 8.1-8.3, wherein the sleep disorder includes sleepmaintenance insomnia, frequent awakenings, and waking up feelingunrefreshed;

-   -   8.11 Any of the foregoing methods, wherein the sleep disorder is        sleep maintenance insomnia;    -   8.12 Any of the foregoing methods, wherein the effective amount        is 1 mg-10 mg per day, e.g., 1-5 mg, preferably 2.5-5 mg, per        day, still preferably 10 mg per day;    -   8.13 Any of the foregoing methods, wherein the effective amount        is 2.5 mg or 5 mg, per day or 10 mg per day;    -   8.14 Any of the foregoing methods wherein the sleep disorder is        in a patient suffering from or at risk of dyskinesia, e.g., a        patient receiving dopaminergic medications, e.g., selected from        levodopa and levodopa adjuncts (carbidopa, COMT inhibitors,        MAO-B inhibitors), dopamine agonists, e.g., receiving levodopa,        and anticholinergics;    -   8.15 Any of the foregoing methods wherein the patient suffers        from Parkinson's disease.

The Compounds of the Invention (e.g., a compound of Formulas I to IV or1.1-1.8) provide effective treatment of 5-HT_(2A), SERT and/or D₂receptor related disorders without or with minimal extrapyramidal sideeffects as similarly disclosed and claimed in WO 2009/145900, thecontents of which are incorporated by reference in their entirety.Therefore, the Compounds of the Invention, the PharmaceuticalCompositions of the Invention or the Depot Compositions of the Inventionmay be used in combination with a second therapeutic agent, particularlyat lower dosages than when the individual agents are used as amonotherapy so as to enhance the therapeutic activities of the combinedagents without causing the undesirable side effects commonly occur inconventional monotherapy. Therefore, the Compounds of the Invention maybe simultaneously, sequentially, or contemporaneously administered withother anti-depressant, anti-psychotic, other hypnotic agents, and/oragents use to treat Parkinson's disease or mood disorders or dementia.In another example, side effects may be reduced or minimized byadministering a Compound of the Invention in combination with one ormore second therapeutic agents in free or salt form, wherein the dosagesof (i) the second therapeutic agent(s) or (ii) both Compound of theInvention and the second therapeutic agent, are lower than if theagent/compound are administered as a monotherapy. In a particularembodiment, the Compounds of the Invention are useful to treatdyskinesia in a patient receiving dopaminergic medications, e.g.,selected from levodopa and levodopa adjuncts (carbidopa, COMTinhibitors, MAO-B inhibitors), dopamine agonists, e.g., such as are usedin the treatment of Parkinson's disease, and anticholinergics used totreat side effects of Parkinson's disease medications.

Therefore, in a sixth aspect, the current invention provides Method I orI_(P), e.g., or any of formulae 7.1-7.32, or Method II or any of8.1-8.15, further comprises one or more therapeutic agents selected fromcompounds that modulate GABA activity (e.g., enhances the activity andfacilitates GABA transmission), a GABA-B agonist, a 5-HT modulator(e.g., a 5-HT_(1A) agonist, a 5-HT_(2A) antagonist, a 5-HT_(2A) inverseagonist, etc.), a melatonin agonist, an ion channel modulator (e.g.,blocker), a serotonin-2 receptor antagonist/reuptake inhibitor (SARIs),an orexin receptor antagonist, an H3 agonist or antagonist, anoradrenergic agonist or antagonist, a galanin agonist, a CRHantagonist, human growth hormone, a growth hormone agonist, estrogen, anestrogen agonist, a neurokinin-1 drug, an anti-depressant, and anantipsychotic agent, e.g., an atypical antipsychotic agent, in free orpharmaceutically acceptable salt form (Method I-A and II-Arespectively).

In another embodiment of the sixth aspect, Method I-A and II-A, MethodI, Method I_(P), e.g., or any of formulae 7.1-7.32, or Method II or anyof 8.1-8.15, further comprises one or more therapeutic agents selectedfrom a cholinesterase inhibitor (e.g., acetylcholinesterase inhibitor)or an N-Methyl D-Aspartate (NMDA) receptor antagonist, in free orpharmaceutically acceptable salt form. In a specific embodiment, thecholinesterase inhibitor (e.g., acetylcholinesterase inhibitor) isselected from the group consisting of Tacrine, rivastigmine (Exelon),donepezil (Aricept), and galantamine (Razadyne, formerly calledReminyl)) in free or pharmaceutically acceptable salt form. In a furtherembodiment, the cholinesterase inhibitor (e.g., acetylcholinesteraseinhibitor) is donepezil in free or pharmaceutically acceptable saltform. In another embodiment, the NMDA receptor antagonist is memantinein free or pharmaceutically acceptable salt form.

In a further embodiment of the sixth aspect, the invention providesMethod I-A or II-A as follows, further comprising one or moretherapeutic agents.

-   -   9.1 Method I-A or II-A, wherein the therapeutic agent(s) is        compounds that modulate GABA activity (e.g., enhances the        activity and facilitates GABA transmission);    -   9.2 Method I-A or II-A or 9.1, wherein the GABA compound is        selected from a group consisting of one or more of doxepin,        alprazolam, bromazepam, clobazam, clonazepam, clorazepate,        diazepam, flunitrazepam, fiurazepam, lorazepam, midazolam,        nitrazepam, oxazepam, temazapam, triazolam, indiplon, zopiclone,        eszopiclone, zaleplon, Zolpidem, gabaxadol, vigabatrin,        tiagabine, EVT 201 (Evotec Pharmaceuticals) and estazolam;    -   9.3 Method I-A or II-A, wherein the therapeutic agent is an        additional 5HT2A antagonist;    -   9.4 Method I-A or II-A or 9.3, wherein said additional 5HT_(2A)        antagonist is selected from one or more of ketanserin,        risperidone, eplivanserin, volinanserin (Sanofi-Aventis,        France), pruvanserin, MDL 100907 (Sanofi-Aventis, France), HY        10275 (Eli Lilly), APD 125 (Arena Pharmaceuticals, San Diego,        Calif.), and AVE8488 (Sanofi-Aventis, France); Method I-A or        II-A, 9.3 or 9.4 additionally selected from pimavanserin        (ACP-103) and pizotifen;    -   9.5 Method I-A or II-A, wherein the therapeutic agent is a        melatonin agonist;    -   9.6 Method I-A or II-A or 9.5, wherein the melatonin agonist is        selected from a group consisting of one or more of melatonin,        ramelteon (ROZEREM®, Takeda Pharmaceuticals, Japan), VEC-162        (Vanda Pharmaceuticals, Rockville, Md.), PD-6735 (Phase II        Discovery) and agomelatine;    -   9.7 Method I-A or II-A, wherein the therapeutic agent is an ion        channel blocker;    -   9.8 Method I-A or II-A or 9.7, wherein said ion channel blocker        is one or more of lamotrigine, gabapentin and pregabalin.    -   9.9 Method I-A or II-A, wherein the therapeutic agent is an        orexin receptor antagonist;    -   9.10 Method I-A or II-A or 9.9, wherein the orexin receptor        antagonist is selected from a group consisting of orexin, a        1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK), GW649868        (GlaxoSmithKline) and a benzamide derivative;    -   9.11 Method I-A or II-A, wherein the therapeutic agent is the        serotonin-2 receptor antagonist/reuptake inhibitor (SARI);    -   9.12 Method I-A or II-A or 9.11, wherein the serotonin-2        receptor antagonist/reuptake inhibitor (SARI) is selected from a        group consisting of one or more Org 50081 (Organon-Netherlands),        ritanserin, nefazodone, serzone and trazodone;    -   9.13 Method I-A or II-A, wherein the therapeutic agent is the        5HT1a agonist;    -   9.14 Method I-A or II-A or 9.13, wherein the 5HT_(1a) agonist is        selected from a group consisting of one or more of repinotan,        sarizotan, eptapirone, buspirone and MN-305 (MediciNova, San        Diego, Calif.);    -   9.15 Method I-A or II-A, wherein the therapeutic agent is the        neurokinin-1 drug;    -   9.16 Method I-A or II-A or 9.15, wherein the neurokinin-1 drug        is Casopitant (GlaxoSmithKline);    -   9.17 Method I-A or II-A, wherein the therapeutic agent is an        antipsychotic agent;    -   9.18 Method I-A or II-A or 9.17, wherein the antipsychotic agent        is selected from a group consisting of chlorpromazine,        haloperidol, droperidol, fluphenazine, loxapine, mesoridazine,        molindone, perphenazine, pimozide, prochlorperazine promazine,        thioridazine, thiothixene, trifluoperazine, clozapine,        aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone        and paliperidone;    -   9.19 Method I-A or II-A, wherein the therapeutic agent is an        anti-depressant;    -   9.20 Method I-A or II-A or 9.19, wherein the anti-depressant is        selected from amitriptyline, amoxapine, bupropion, citalopram,        clomipramine, desipramine, doxepin, duloxetine, escitalopram,        fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline,        mirtazapine, nefazodone, nortriptyline, paroxetine, phenelazine        sulfate, protriptyline, sertraline, tranylcypromine, trazodone,        trimipramine, and venlafaxine;    -   9.21 Method I-A or II-A, 9.17 or 9.18, wherein the antipsychotic        agent is an atypical antipsychotic agent;    -   9.22 Method I-A or II-A, or any of 9.17-9.21, wherein the        atypical antipsychotic agent is selected from a group consisting        of clozapine, aripiprazole, olanzapine, quetiapine, risperidone,        ziprasidone, and paliperidone;    -   9.23 Method I-A or II-A, wherein the therapeutic agent is        selected from any of methods 9.1-9.22, e.g., selected from a        group consisting of modafinil, armodafinil, doxepin, alprazolam,        bromazepam, clobazam, clonazepam, clorazepate, diazepam,        flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam,        oxazepam, temazapam, triazolam, indiplon, zopiclone,        eszopiclone, zaleplon, Zolpidem, gabaxadol, vigabatrin,        tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam,        ketanserin, risperidone, eplivanserin, volinanserin        (Sanofi-Aventis, France), pruvanserin, MDL 100907        (Sanofi-Aventis, France), HY 10275 (Eli Lilly), APD 125 (Arena        Pharmaceuticals, San Diego, Calif.), AVE8488 (Sanofi-Aventis,        France), repinotan, sarizotan, eptapirone, buspirone, MN-305        (MediciNova, San Diego, Calif.), melatonin, ramelteon (ROZEREM®,        Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals,        Rockville, Md.), PD-6735 (Phase II Discovery), agomelatine,        lamotrigine, gabapentin, pregabalin, orexin, a 1,3-biarylurea,        SB-334867-a (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline), a        benzamide derivative, Org 50081 (Organon-Netherlands),        ritanserin, nefazodone, serzone, trazodone, Casopitant        (GlaxoSmithKline), amitriptyline, amoxapine, bupropion,        citalopram, clomipramine, desipramine, doxepin, duloxetine,        escitalopram, fluoxetine, fluvoxamine, imipramine,        isocarboxazid, maprotiline, mirtazapine, nefazodone,        nortriptyline, paroxetine, phenelazine sulfate, protriptyline,        sertraline, tranylcypromine, trazodone, trimipramine,        venlafaxine, chlorpromazine, haloperidol, droperidol,        fluphenazine, loxapine, mesoridazine molindone, perphenazine,        pimozide, prochlorperazine promazine, thioridazine, thiothixene,        trifluoperazine, clozapine, aripiprazole, olanzapine,        quetiapine, risperidone, ziprasidone and paliperidone; In        addition to the therapeutic agents listed herewith, Method I-A        or II-A, is further selected from pimavanserin (ACP-103) and        pizotifen;    -   9.24 Method I-A or II-A wherein the therapeutic agent is an H3        agonist;    -   9.25 Method I-A or II-A, wherein the therapeutic agent is an H3        antagonist;    -   9.26 Method I-A or II-A, wherein the therapeutic agent is a        noradrenergic agonist or antagonist;    -   9.27 Method I-A or II-A, wherein the therapeutic agent is a        galanin agonist;    -   9.28 Method I-A or II-A, wherein the therapeutic agent is a CRH        antagonist;    -   9.29 Method I-A or II-A, wherein the therapeutic agent is a        human growth hormone;    -   9.30 Method I-A or II-A, wherein the therapeutic agent is a        growth hormone agonist;    -   9.31 Method I-A or II-A, wherein the therapeutic agent is        estrogen or an estrogen agonist;    -   9.32 Method I-A or II-A, wherein the therapeutic agent is 5-HT₆        receptor antagonist;    -   9.33 Method I-A or II-A, wherein the therapeutic agent is a        neurokinin-1 drug;    -   9.34 Method I-A or II-A, wherein a therapeutic agent is combined        with compounds of Formula (I) and the therapeutic agent is an        anti-Parkinson agent such as L-dopa, co-careldopa, duodopa,        stalova, Symmetrel, benzotropine, biperiden, bromocryiptine,        entacapone, pergolide, pramipexole, procyclidine, ropinirole,        selegiline and tolcapone;    -   9.35 Method I-A or II-A, wherein compounds of Formula (I) may be        used to treat sleep disorders, depression, psychosis, or any        combinations thereof, in patients suffering from the listed        diseases and/or Parkinson's disease;    -   9.36 Method I-A or II-A, wherein the disorder is selected from        at least one or more of psychosis, e.g., schizophrenia,        depression, mood disorders, sleep disorders (e.g., sleep        maintenance and/or sleep onset) or any combination of disorders        thereof;    -   9.37 Any of the foregoing methods wherein the disorder is sleep        disorder;    -   9.38 Any of the foregoing methods, wherein the disorder is sleep        disorder associated with psychosis, e.g., schizophrenia or        Parkinson's disease; in free or pharmaceutically acceptable salt        form.

In another embodiment of the sixth aspect, the current inventionprovides Method I_(P) or Method II as hereinbefore described, furthercomprises one or more therapeutic agents selected from compounds thatmodulate GABA activity (e.g., enhances the activity and facilitates GABAtransmission), a GABA-B agonist, a 5-HT modulator (e.g., a 5-HT_(1A)agonist, a 5-HT_(2A) antagonist, a 5-HT_(2A) inverse agonist, etc.), amelatonin agonist, an ion channel modulator (e.g., blocker), aserotonin-2 antagonist/reuptake inhibitor (SARIs), an orexin receptorantagonist, an H3 agonist or antagonist, a noradrenergic agonist orantagonist, a galanin agonist, a CRH antagonist, human growth hormone, agrowth hormone agonist, estrogen, an estrogen agonist, a neurokinin-1drug, an anti-depressant, and an antipsychotic agent, e.g., an atypicalantipsychotic agent, in free or pharmaceutically acceptable salt form(Method I_(P)-A and II-A respectively). In a further embodiment of thisaspect, the invention provides Method I_(P)-A or II-A as similarlydescribed in any one of formulae 9.1-9.38.

In still another embodiment of the sixth aspect, Method I_(P) or MethodII as hereinbefore described further comprises one or more therapeuticagents selected from a cholinesterase inhibitor (e.g.,acetylcholinesterase inhibitor) or an N-Methyl D-Aspartate (NMDA)receptor antagonist, in free or pharmaceutically acceptable salt form.In a specific embodiment, the cholinesterase inhibitor (e.g.,acetylcholinesterase inhibitor) is selected from the group consisting ofTacrine, rivastigmine (Exelon), donepezil (Aricept), and galantamine(Razadyne, formerly called Reminyl)) in free or pharmaceuticallyacceptable salt form. In a further embodiment, the cholinesteraseinhibitor (e.g., acetylcholinesterase inhibitor) is donepezil in free orpharmaceutically acceptable salt form. In another embodiment, the NMDAreceptor antagonist is memantine in free or pharmaceutically acceptablesalt form.

In a seventh aspect of the invention, the combination of a Compound ofthe Invention and one or more second therapeutic agents as described inMethods I-A, II-A or any of 9.1-9.38, may be administered as aPharmaceutical Composition or a depot Composition as hereinbeforedescribed. Similarly, the combination of a Compound of the Invention andone or more second therapeutic agents as described in Methods I_(p)-A,II-A or any of 9.1-9.38, may be administered as a PharmaceuticalComposition or a depot Composition as hereinbefore described. Thecombination compositions can include mixtures of the combined drugs, aswell as two or more separate compositions of the drugs, which individualcompositions can be, for example, co-administered together to a patient.

In a particular embodiment, Methods I-A, II-A, I_(p)-A, II-A or any of9.1-9.38 comprises administering to a patient in need thereof, aCompound of the Invention in combination with an atypical antipsychoticagent, e.g., a compound selected from clozapine, aripiprazole,olanzapine, quetiapine, risperidone, ziprasidone, or paliperidone, infree or pharmaceutically acceptable salt form, for example wherein thedosage of the atypical antipsychotic agent is reduced and/or sideeffects are reduced.

In another embodiment, Methods I-A, II-A, Methods I_(p)-A, II-A or anyof 9.1-9.38 comprises administering to a patient in need thereof, aCompound of the Invention in combination with an anti-depressant, e.g.,amitriptyline, amoxapine, bupropion, citalopram, clomipramine,desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine,imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone,nortriptyline, paroxetine, phenelazine sulfate, protriptyline,sertraline, tranylcypromine, trazodone, trimipramine, or venlafaxine, infree or pharmaceutically acceptable salt form. Alternatively, theanti-depressant may be used as an adjunct medication in addition to thecompounds of the Invention.

In still another embodiment, Methods I-A, II-A, I_(p)-A, II-A or any of9.1-9.38 comprises administering to a patient in need thereof, aCompound of the Invention in combination with a compound that modulatesGABA activity, e.g., a compound selected from doxepin, alprazolam,bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam,flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazapam,triazolam, indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem,gabaxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals),estazolam or any combinations thereof, in free or pharmaceuticallyacceptable salt form.

In another particular embodiment, Methods I-A, II-A, I_(p)-A, II-A orany of 9.1-9.38 comprises administering to a patient in need thereof, aCompound of the Invention in combination with doxepin in free orpharmaceutically acceptable salt form. Dosages of doxepin can vary inany range known to a person of ordinary skill in the art. In oneexample, a 10 mg dose of doxepin may be combined with any dosage of acompound of the Invention.

In another embodiment, Methods I-A, II-A, I_(p)-A, II-A or any of9.1-9.38 comprises administering to a patient in need thereof, aCompound of the Invention in combination (including as part of a dailydosage regimen) with an atypical stimulant, e.g., a modafinil,adrafinil, or armodafinil. A regimen incorporating a Compound of theInvention with such drugs promotes more regular sleep, and avoids sideeffects such as psychosis or mania associated with higher levels of suchdrugs, e.g., in the treatment of bipolar depression, cognitionassociated with schizophrenia, and excessive sleepiness and fatigue inconditions such as Parkinson's disease and cancer.

In an eighth aspect, the invention provides use of a compound asdescribed in the following formulae:

-   -   11.1 Compound of Formula I or any of formulae 1-1.9, in free or        pharmaceutically acceptable salt form;    -   11.2 a Pharmaceutical Composition as hereinbefore described;    -   11.3 Depot Composition as hereinbefore described; or    -   11.4 Osmotic-controlled Release Oral delivery System Composition        as hereinbefore described,        (in the manufacture of a medicament) for the treatment or        prophylaxis of one or more disorders as disclosed hereinbefore,        e.g., in any of Method I, any of 7.1-7.32, Method II, any of        8.1-8.15, Methods I-A, II-A, any of 9.1-9.38, Method I_(P),        Methods I_(P)-A, or any methods described in the sixth or        seventh aspect of the invention.

In a ninth aspect, the invention provides a pharmaceutical compositionas hereinbefore described, e.g., in the following formulae:

-   -   12.1 a Pharmaceutical Composition as hereinbefore described;    -   12.2 Depot Composition as hereinbefore described; or    -   12.3 Osmotic-controlled Release Oral delivery System Composition        as hereinbefore described,        for use in the treatment or prophylaxis of one or more disorders        as disclosed hereinbefore, e.g., in any of Method I, any of        7.1-7.32, Method II, any of 8.1-8.15, Methods I-A, II-A, any of        9.1-9.38, Method I_(P), Methods I_(P)-A, or any methods        described in the sixth or seventh aspect of the invention.

In particular embodiments of any of the methods hereinbefore described,including any preceding embodiments of the fourth aspect (includingMethod I and any of Methods 7.1-7.32), the fifth aspect (includingMethod II and any of Methods 8.1-8.15), Method I_(P), Methods I_(P)-A,the sixth aspect (including Method I-A, II-A and any of Methods9.1-9.38), and the seventh aspect, the disorders and conditions referredto have their meaning as defined in the American PsychiatricAssociation's Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition (DSM-V) (2013).

In other particular embodiments of any of the methods hereinbeforedescribed, including any preceding embodiments of the fourth aspect(including Method I and any of Methods 7.1-7.32), the fifth aspect(including Method II and any of Methods 8.1-8.15), Method I_(P), MethodsI_(P)-A, the sixth aspect (including Method I-A, II-A and any of Methods9.1-9.38), and the seventh aspect, the disorders and conditions referredto have their meaning as defined in the World Health Organization'sInternational Classification of Diseases, Tenth Revision (ICD-10),Chapter V (Mental and Behavioral Disorders) (1992).

DETAILED DESCRIPTION OF THE INVENTION

If not otherwise specified or clear from context, the following terms asused herein have the following meetings:

-   -   a. “Residual symptoms” as used herein include negative symptoms        and general psychopathology symptoms as described in the        Positive and Negative Symptom Scale (PANSS) for Schizophrenia        described in Kay et al., Schizophr. Bull. (1987) 13(2):261-276,        the contents of which are incorporated by reference in their        entirety. Negative symptoms include: blunted affect, emotional        withdrawal, poor rapport, passive/apathetic social withdrawal,        difficulty in abstract thinking, lack of spontaneity and flow of        conversation and stereotyped thinking General psychopathology        symptoms include: somatic concern, anxiety, guilt feelings,        tension, mannerisms and posturing, depression, motor        retardation, uncooperativeness, unusual thought content,        disorientation, poor attention, lack of judgment and insight,        disturbance of volition, poor impulse control, preoccupation and        active social avoidance. Residual symptoms may also include        depression, cognitive impairment and sleep disorders (e.g.,        insomnia). Of these residual symptoms, the compounds of the        invention are particularly useful for the treatment of passive        social withdrawal, stereotyped thinking, somatic concerns,        anxiety, tension, active social avoidance and depression.        Therefore, the compounds of the present invention are        particularly useful in improving social integration and social        function in patients suffering from schizophrenia. Treatment of        these residual symptoms is also particularly effective in        schizophrenic patients also suffering from depression.    -   b. As used in a formula, for example in the structure of any of        Formulas I-IV or 1.1-1.8, and in a term such as “CD3”, “D”        refers to an atom of hydrogen which contains more than the        natural abundance of the isotope deuterium (²H). All naturally        occurring chemical compound include hydrogen atoms containing        approximately 0.0156 atom % deuterium for every hydrogen atom.        The use of “D” and “deuterium” in the present disclosure refers        to any enrichment of the amount of deuterium above this natural        abundance, for example, above 0.1%, or above 1%, up to any value        short of 100% (e.g., 99%, or 99.9%, or 99.99%, or 99.999%). The        use of “H” as a hydrogen atom refers to a hydrogen atom in a        chemical structure containing not more than the natural        abundance of deuterium, e.g., not more than 0.0156 atom %        deuterium.

Unless otherwise indicated, the Compounds of the Invention, e.g., acompound of Formulas I to IV or 1.1-1.8, may exist in free or salt,e.g., as acid addition salts, form. An acid-addition salt of a compoundof the invention which is sufficiently basic, for example, anacid-addition salt with, for example, an inorganic or organic acid. In aparticular embodiment, the salt of the Compounds of the Invention is atoluenesulfonic acid addition salt.

The Compounds of the Invention are intended for use as pharmaceuticals,therefore pharmaceutically acceptable salts are preferred. Salts whichare unsuitable for pharmaceutical uses may be useful, for example, forthe isolation or purification of free Compounds of the Invention, andare therefore also included.

The Compounds of the Invention may comprise one or more chiral carbonatoms. The compounds thus exist in individual isomeric, e.g.,enantiomeric or diastereomeric form or as mixtures of individual forms,e.g., racemic/diastereomeric mixtures. Any isomer may be present inwhich the asymmetric center is in the (R)-, (S)-, or(R,S)-configuration. The invention is to be understood as embracing bothindividual optically active isomers as well as mixtures (e.g.,racemic/diastereomeric mixtures) thereof. Accordingly, the Compounds ofthe Invention may be a racemic mixture or it may be predominantly, e.g.,in pure, or substantially pure, isomeric form, e.g., greater than 70%enantiomeric/diastereomeric excess (“ee”), preferably greater than 80%ee, more preferably greater than 90% ee, most preferably greater than95% ee. The purification of said isomers and the separation of saidisomeric mixtures may be accomplished by standard techniques known inthe art (e.g., column chromatography, preparative TLC, preparative HPLC,simulated moving bed and the like).

Geometric isomers by nature of substituents about a double bond or aring may be present in cis (Z) or trans (E) form, and both isomericforms are encompassed within the scope of this invention.

Alternatively and/or additionally, the Compounds of the Invention may beincluded as a depot formulation, e.g., by dispersing, dissolving orencapsulating the Compounds of the Invention in a polymeric matrix asdescribed in the second and third aspect, such that the Compound iscontinually released as the polymer degrades over time. The release ofthe Compounds of the Invention from the polymeric matrix provides forthe controlled- and/or delayed- and/or sustained-release of theCompounds, e.g., from the pharmaceutical depot composition, into asubject, for example a warm-blooded animal such as man, to which thepharmaceutical depot is administered. Thus, the pharmaceutical depotdelivers the Compounds of the Invention to the subject at concentrationseffective for treatment of the particular disease or medical conditionover a sustained period of time, e.g., 14-180 days, preferably about 30,about 60 or about 90 days.

Polymers useful for the polymeric matrix in the Composition of theInvention (e.g., Depot composition of the Invention) may include apolyester of a hydroxy-fatty acid and derivatives thereof or otheragents such as polylactic acid, polyglycolic acid, polycitric acid,polymalic acid, poly-beta.-hydroxybutyric acid, epsilon.-capro-lactonering opening polymer, lactic acid-glycolic acid copolymer,2-hydroxybutyric acid-glycolic acid copolymer, polylacticacid-polyethylene glycol copolymer or polyglycolic acid-polyethyleneglycol copolymer), a polymer of an alkyl alpha-cyanoacrylate (forexample poly(butyl 2-cyanoacrylate)), a polyalkylene oxalate (forexample polytrimethylene oxalate or polytetramethylene oxalate), apolyortho ester, a polycarbonate (for example polyethylene carbonate orpolyethylenepropylene carbonate), a polyortho-carbonate, a polyaminoacid (for example poly-gamma.-L-alanine, poly-.gamma.-benzyl-L-glutamicacid or poly-y-methyl-L-glutamic acid), a hyaluronic acid ester, and thelike, and one or more of these polymers can be used.

If the polymers are copolymers, they may be any of random, block and/orgraft copolymers. When the above alpha-hydroxycarboxylic acids,hydroxydicarboxylic acids and hydroxytricarboxylic acids have opticalactivity in their molecules, any one of D-isomers, L-isomers and/orDL-isomers may be used. Among others, alpha-hydroxycarboxylic acidpolymer (preferably lactic acid-glycolic acid polymer), its ester,poly-alpha-cyanoacrylic acid esters, etc. may be used, and lacticacid-glycolic acid copolymer (also referred to aspoly(lactide-alpha-glycolide) or poly(lactic-co-glycolic acid), andhereinafter referred to as PLGA) are preferred. Thus, in one aspect thepolymer useful for the polymeric matrix is PLGA. As used herein, theterm PLGA includes polymers of lactic acid (also referred to aspolylactide, poly (lactic acid), or PLA). Most preferably, the polymeris the biodegradable poly(d,l-lactide-co-glycolide) polymer.

In a preferred embodiment, the polymeric matrix of the invention is abiocompatible and biodegradable polymeric material. The term“biocompatible” is defined as a polymeric material that is not toxic, isnot carcinogenic, and does not significantly induce inflammation in bodytissues. The matrix material should be biodegradable wherein thepolymeric material should degrade by bodily processes to productsreadily disposable by the body and should not accumulate in the body.The products of the biodegradation should also be biocompatible with thebody in that the polymeric matrix is biocompatible with the body.Particular useful examples of polymeric matrix materials includepoly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid,copolymers of the foregoing, poly(aliphatic carboxylic acids),copolyoxalates, polycaprolactone, polydioxonone, poly(ortho carbonates),poly(acetals), poly(lactic acid-caprolactone), polyorthoesters,poly(glycolic acid-caprolactone), polyanhydrides, and natural polymersincluding albumin, casein, and waxes, such as, glycerol mono- anddistearate, and the like. The preferred polymer for use in the practiceof this invention is dl-(polylactide-co-glycolide). It is preferred thatthe molar ratio of lactide to glycolide in such a copolymer be in therange of from about 75:25 to 50:50.

Useful PLGA polymers may have a weight-average molecular weight of fromabout 5,000 to 500,000 daltons, preferably about 150,000 daltons.Dependent on the rate of degradation to be achieved, different molecularweight of polymers may be used. For a diffusional mechanism of drugrelease, the polymer should remain intact until all of the drug isreleased from the polymeric matrix and then degrade. The drug can alsobe released from the polymeric matrix as the polymeric excipientbioerodes.

The PLGA may be prepared by any conventional method, or may becommercially available. For example, PLGA can be produced byring-opening polymerization with a suitable catalyst from cycliclactide, glycolide, etc. (see EP-0058481B2; Effects of polymerizationvariables on PLGA properties: molecular weight, composition and chainstructure).

It is believed that PLGA is biodegradable by means of the degradation ofthe entire solid polymer composition, due to the break-down ofhydrolysable and enzymatically cleavable ester linkages under biologicalconditions (for example in the presence of water and biological enzymesfound in tissues of warm-blooded animals such as humans) to form lacticacid and glycolic acid. Both lactic acid and glycolic acid arewater-soluble, non-toxic products of normal metabolism, which mayfurther biodegrade to form carbon dioxide and water. In other words,PLGA is believed to degrade by means of hydrolysis of its ester groupsin the presence of water, for example in the body of a warm-bloodedanimal such as man, to produce lactic acid and glycolic acid and createthe acidic microclimate. Lactic and glycolic acid are by-products ofvarious metabolic pathways in the body of a warm-blooded animal such asman under normal physiological conditions and therefore are welltolerated and produce minimal systemic toxicity.

In another embodiment, the polymeric matrix useful for the invention maycomprise a star polymer wherein the structure of the polyester isstar-shaped. These polyesters have a single polyol residue as a centralmoiety surrounded by acid residue chains. The polyol moiety may be, e.g., glucose or, e. g., mannitol. These esters are known and described inGB 2,145,422 and in U.S. Pat. No. 5,538,739, the contents of which areincorporated by reference.

The star polymers may be prepared using polyhydroxy compounds, e. g.,polyol, e. g., glucose or mannitol as the initiator. The polyol containsat least 3 hydroxy groups and has a molecular weight of up to about20,000 Daltons, with at least 1, preferably at least 2, e. g., as a mean3 of the hydroxy groups of the polyol being in the form of ester groups,which contain polylactide or co-polylactide chains. The branchedpolyesters, e. g., poly (d,l-lactide-co-glycolide) have a centralglucose moiety having rays of linear polylactide chains.

The depot composition of the invention as hereinbefore described maycomprise the polymer in the form of microparticles or nanoparticles, orin a liquid form, with the Compounds of the Invention dispersed orencapsulated therein. “Microparticles” is meant solid particles thatcontain the Compounds of the Invention either in solution or in solidform wherein such compound is dispersed or dissolved within the polymerthat serves as the matrix of the particle. By an appropriate selectionof polymeric materials, a microparticle formulation can be made in whichthe resulting microparticles exhibit both diffusional release andbiodegradation release properties.

In a particular embodiment, the Compound of the Invention is formulatedinto microparticles of an appropriate size to allow slow releasekinetics after intramuscular injection.

When the polymer is in the form of microparticles, the microparticlesmay be prepared using any appropriate method, such as by a solventevaporation or solvent extraction method. For example, in the solventevaporation method, the Compounds of the Invention and the polymer maybe dissolved in a volatile organic solvent (for example a ketone such asacetone, a halogenated hydrocarbon such as chloroform or methylenechloride, a halogenated aromatic hydrocarbon, a cyclic ether such asdioxane, an ester such as ethyl acetate, a nitrile such as acetonitrile,or an alcohol such as ethanol) and dispersed in an aqueous phasecontaining a suitable emulsion stabilizer (for example polyvinylalcohol, PVA). The organic solvent is then evaporated to providemicroparticles with the Compounds of the Invention encapsulated therein.In the solvent extraction method, the Compounds of the Invention andpolymer may be dissolved in a polar solvent (such as acetonitrile,dichloromethane, methanol, ethyl acetate or methyl formate) and thendispersed in an aqueous phase (such as a water/PVA solution). Anemulsion is produced to provide microparticles with the Compounds of theInvention encapsulated therein. Spray drying is an alternativemanufacturing technique for preparing the microparticles.

Another method for preparing the microparticles of the invention is alsodescribed in both U.S. Pat. Nos. 4,389,330 and 4,530,840, the contentsof which are incorporated by reference.

The microparticle of the present invention can be prepared by any methodcapable of producing microparticles in a size range acceptable for usein an injectable composition. One preferred method of preparation isthat described in U.S. Pat. No. 4,389,330. In this method the activeagent is dissolved or dispersed in an appropriate solvent. To theagent-containing medium is added the polymeric matrix material in anamount relative to the active ingredient that provides a product havingthe desired loading of active agent. Optionally, all of the ingredientsof the microparticle product can be blended in the solvent mediumtogether.

Solvents for the Compounds of the Invention and the polymeric matrixmaterial that can be employed in the practice of the present inventioninclude organic solvents, such as acetone; halogenated hydrocarbons,such as chloroform, methylene chloride, and the like; aromatichydrocarbon compounds; halogenated aromatic hydrocarbon compounds;cyclic ethers; alcohols, such as, benzyl alcohol; ethyl acetate; and thelike. In one embodiment, the solvent for use in the practice of thepresent invention may be a mixture of benzyl alcohol and ethyl acetate.Further information for the preparation of microparticles useful for theinvention can be found in U.S. Patent Publication Number 2008/0069885,the contents of which are incorporated herein by reference in theirentirety.

The amount of the Compounds of the Invention incorporated in themicroparticles usually ranges from about 1 wt % to about 90 wt. %,preferably 30 to 50 wt. %, more preferably 35 to 40 wt. %. By weight %is meant parts of the Compounds of the Invention per total weight ofmicroparticle.

The pharmaceutical depot may comprise a pharmaceutically-acceptablediluent or carrier, such as a water miscible diluent or carrier.

Details of Osmotic-controlled Release Oral delivery System compositionmay be found in EP 1 539 115 (U.S. Pub. No. 2009/0202631) and WO2000/35419, the contents of each of which are incorporated by referencein their entirety.

A “therapeutically effective amount” is any amount of the Compounds ofthe invention (for example as contained in the pharmaceutical depot)which, when administered to a subject suffering from a disease ordisorder, is effective to cause a reduction, remission, or regression ofthe disease or disorder over the period of time as intended for thetreatment.

Dosages employed in practicing the present invention will of course varydepending, e.g. on the particular disease or condition to be treated,the particular Compounds of the Invention used, the mode ofadministration, and the therapy desired.

Compounds of the Invention may be administered by any satisfactoryroute, including orally, parenterally (intravenously, intramuscular orsubcutaneous) or transdermally, but are preferably administered orally.In certain embodiments, the Compounds of the Invention, e.g., in depotformulation, is preferably administered parenterally, e.g., byinjection.

In general, satisfactory results for Method I or any of formulae7.1-7.32 or Method I_(P) or use of the Compounds of the Invention ashereinbefore described, e.g. for the treatment of a combination ofdiseases such as a combination of at least depression, psychosis, e.g.,(1) psychosis, e.g., schizophrenia, in a patient suffering fromdepression; (2) depression in a patient suffering from psychosis, e.g.,schizophrenia; (3) mood disorders associated with psychosis, e.g.,schizophrenia, or Parkinson's disease; and (4) sleep disordersassociated with psychosis, e.g., schizophrenia, or Parkinson's disease,as set forth above are indicated to be obtained on oral administrationat dosages of the order from about 1 mg to 100 mg once daily, preferablyabout 2.5 mg-50 mg, e.g., 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg or 50mg, once daily, preferably via oral administration.

Satisfactory results for Method II or any of 8.1-8.15, Method II or useof the Compounds of the Invention as hereinbefore described, e.g. forthe treatment of sleep disorder alone or agitation, aggressivebehaviors, post-traumatic stress disorder or impulse control disorderalone, e.g., intermittent explosive disorder alone are indicated to beobtained on oral administration at dosages of the order from about 1mg-10 mg once daily, e.g., about 2.5 mg-5 mg, e.g., 2.5 mg, 3 mg, 4 mg,5 mg or 10 mg, of a Compound of the Invention, in free orpharmaceutically acceptable salt form, once daily, preferably via oraladministration.

Satisfactory results for Method I-A or any of 9.1-9.38 or Method I_(P)-Aare indicated to be obtained at less than 100 mg, preferably less than50 mg, e.g., less than 40 mg, less than 30 mg, less than 20 mg, lessthan 10 mg, less than 5 mg, less than 2.5 mg, once daily. Satisfactoryresults for Method II-A or any of 9.1-9.38 are indicated to be obtainedat less than 10 mg, e.g., less than 5 mg or, preferably less than 2.5mg.

For treatment of the disorders disclosed herein wherein the depotcomposition is used to achieve longer duration of action, the dosageswill be higher relative to the shorter action composition, e.g., higherthan 1-100 mg, e.g., 25 mg, 50 mg, 100 mg, 500 mg, 1,000 mg, or greaterthan 1000 mg. In a particular embodiment, the dosage regimen for depotcomposition includes an initial oral immediate dose along with depotrelease so as to provide a steady-state blood level of the drug.Duration of action of the Compounds of the Invention may be controlledby manipulation of the polymer composition, i.e., the polymer:drug ratioand microparticle size. Wherein the composition of the invention is adepot composition, administration by injection is preferred.

The pharmaceutically acceptable salts of the Compounds of the Inventioncan be synthesized from the parent compound which contains a basic oracidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free base forms of these compounds witha stoichiometric amount of the appropriate acid in water or in anorganic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Further details for the preparation of these salts, e.g.,toluenesulfonic salt in amorphous or crystal form, may be found inPCT/US08/03340 and/or U.S. Provisional Appl. No. 61/036,069.

Pharmaceutical compositions comprising Compounds of the Invention may beprepared using conventional diluents or excipients (an example include,but is not limited to sesame oil) and techniques known in the galenicart. Thus oral dosage forms may include tablets, capsules, solutions,suspensions and the like.

All references herein to dosage, dosage rate or therapeutically effectamount of a Compound or Composition of the Invention refers to theequivalent free-base moiety in the dosage, excluding any salts.

Methods of Making the Compounds of the Invention

The intermediates of the Compounds of the Invention may generally beprepared as described in in WO PCT/US08/03340 (WO 2008/112280); U.S.application Ser. No. 10/786,935; U.S. Pat. Nos. 6,548,493; 7,238,690;6,552,017; 6,713,471; 7,183,282; U.S. RE39680, and U.S. RE39679, and WO2015/154025, the contents of each of which are incorporated by referencein their entirety. Salts of the Compounds of the Invention may also beprepared as similarly described in U.S. Pat. Nos. 6,548,493; 7,238,690;6,552,017; 6,713,471; 7,183,282; U.S. RE39680; U.S. RE39679; and WO2009/114181, the contents of each of which are incorporated by referencein their entirety.

Isolation or purification of the diastereomers of the Compounds of theInvention may be achieved by conventional methods known in the art,e.g., column purification, preparative thin layer chromatography,preparative HPLC, crystallization, trituration, simulated moving bedsand the like.

Example 11-(4-Fluorophenyl)-4-((6bR,10aS)-3-methyl-d₃-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-onep-toluenesulfonate

To a suspension of (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′, 4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8-carboxylic acid ethyl ester (4.27 g,14.2 mmol) in DMF (70 mL) is added NaH (560 mg, 95%, 21.3 mmol) inbatches at room temperature. The suspension is then stirred at roomtemperature for 30 min until a clear light red solution is obtained.After the solution is cooled to 0-5° C., CD₃I (982 μL, 17.0 mmol) in DMF(1 mL) is added. The reaction mixture is stirred at 0-5° C. until all ofthe starting material is consumed. After quenching by ice, the mixtureis acidified to pH of 3-5 with HCl (12 N, 0.2 mL) and then concentratedunder reduced pressure. The obtained residue is suspended in a mixtureof dichloromethane (100 mL) and H₂O (50 mL) and then adjusted to pH≥14with 50% NaOH. The organic phase is separated and then concentrated todryness to give 5 g of the crude (6bR,10aS)-ethyl3-methyl-d3-2-oxo-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3′, 4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(9H)-carboxylate as a brown solid,which is used directly in the next step without further purification. MS(ESI) m/z 319.2 [M+H]⁺.

To a stirred solution of (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′, 4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8-carboxylic acid ethyl ester (3.09 g,9.71 mmol) in THF (20 mL) is added BH₃ in THF (50 mL, 1.0 M, 50.0 mmol)at room temperature. The mixture is stirred at room temperature for 36h, and then is cooled to 0-5° C., followed by quenching with MeOH (5mL). The solvents are removed under reduced pressure to give a lightyellow residue. To the residue is added HCl (12 N, 35 mL) at roomtemperature. The resulting mixture is stirred at 95° C. for 30 h, cooledto 0-5° C. and is then adjusted to a pH of ≥14 with NaOH (10 N). Themixture is extracted with dichloromethane (100 mL). The combined organicphase is dried over K₂CO₃ and then concentrated to dryness to afford(6bR,10aS)-3-methyl-d₃-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′, 4′:4,5]pyrrolo[1,2,3-de]quinoxaline as a brown oil, which is used directlyin the next step without further purification. MS (ESI) m/z 233.2[M+H]⁺.

A suspension of(6bR,10aS)-3-methyl-d₃-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′, 4′:4,5]pyrrolo[1,2,3-de]quinoxaline (1.6 g, 6.89 mmol), K₂CO₃ (2.0 g), KI(1.7 g) and 4-chloro-4′-fluorobutyrophenone (2.3 mL) in 3-pentanone (80mL) is degassed by bubbling Argon for 10 min. After N,N-diisopropylethylamine (1.2 mL, 6.89 mmol) is added, the reactionmixture is stirred at 75° C. for 36 h. After the mixture is cooled toroom temperature, the solvent is removed. The residue is suspended indichloromethane (500 mL) and then is washed with H₂O twice (160 mL). Theorganic phase is dried over K₂CO₃ and then evaporated to dryness. Theresidue is purified by silica gel flash chromatography using a gradientof 0-100% ethyl acetate in a mixture of ethyl acetate and methanol(10:1) with 1% TEA as an eluent to afford1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-d₃-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one as a brown oil(1.66 g, 61% yield). MS (ESI) m/z 397.2 [M+H]⁺.

To a solution of1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-d₃-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one (1.52 g, 3.83 mmol)in isopropyl alcohol (5.4 mL) is slowly added a solution ofp-toluenesulfonic acid monohydrate (656 mg, 3.45 mmol) in 2.1 mL ofisopropyl alcohol at room temperature. The reaction mixture is stirredat room temperature until a gel-like suspension is formed. Isopropylalcohol (5.0 mL) is added and the mixture is stirred at room temperaturefor additional 2 h. After filtration, the filter cake is washed withisopropyl alcohol (2.5 mL). The cake is dried under vacuum to yield thetitle compound as a white powder (1.75 g, 80% yield). ¹H NMR (500 MHz,DMSO-d₆) δ 9.1 (s, 1H), 8.1 (ddd, J=2.73, 5.44, 8.68 Hz, 2H), 7.6-7.4(m, 2H), 7.4-7.3 (m, 2H), 7.1 (d, J=7.81 Hz, 2H), 6.6 (t, J=7.62 Hz,1H), 6.4 (d, J=7.89 Hz, 1H), 3.6 (dd, J=6.34, 12.15 Hz, 1H), 3.5-3.4 (m,3H), 3.4-3.3 (m, 2H), 3.3-3.2 (m, 1H), 3.2-3.0 (m, 5H), 2.7 (td, J=3.04,10.27 Hz, 1H), 2.7-2.5 (m, 1H), 2.3 (s, 3H), 2.3-2.2 (m, 1H), 2.0 (m,3H).

Example 22,2-D₂-1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one

To a suspension of (6bR,10aS)-3-Methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8-carboxylic acid ethyl ester (945 mg,3 mmol) in THF (5 mL) is slowly added BD₃-THF (1.0 M in THF, 10 mL, 10mmol) at room temperature. After completion of the addition, thereaction mixture is stirred at room temperature overnight and thencarefully quenched with D₂O (2.0 mL). The solvent is removed undervacuum and the residue is suspended in HCl (12 N, 9 mL). After stirredat 95° C. for 20 h, the reaction mixture is cooled to room temperatureand then adjusted to pH of 12 with 50% NaOH. The mixture is concentratedto dryness to give 2,2-d₂-(6bR,10aS)-3-Methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1, 2,3-de]quinoxaline as a brown solid, which is useddirectly for next step without further purification. MS (ESI) m/z 232.2[M+H]⁺.

To a solution of 2,2-d₂-(6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline (200 mg, 0.87 mmol) in 3-pentanone (6mL) is added KI (290 mg, 1.75 mmol) and 4-chloro-4′-fluorobutyrophenone(0.29 mL, 1.75 mmol), followed by N, N-diisopropylethylamine (0.16 mL,1.75 mmol). The resulting mixture is stirred at 75° C. for 20 h. Afterthe solvent is removed under reduced pressure, the obtained residue ispurified by silica gel column chromatography using a gradient of 0-100%ethyl acetate in a mixture of ethyl acetate and methanol (10:1) with 2%TEA as an eluent to afford the title compound as a brown oil. (47 mg,14% yield). ¹H NMR (500 MHz, CDCl₃) δ8.00 (dd, J=8.9, 5.4 Hz, 2H), 7.13(t, J=8.6 Hz, 2H), 6.65 (t, J=7.6 Hz, 1H), 6.51 (d, J=6.6 Hz, 1H), 6.41(d, J=7.8 Hz, 1H), 3.29 (d, J=10.1 Hz, 1H), 3.25-3.14 (m, 2H), 3.02 (t,J=7.1 Hz, 2H), 2.98-2.90 (m, 1H), 2.86 (s, 3H), 2.84-2.69 (m, 2H),2.61-2.23 (m, 3H), 2.17-1.86 (m, 5H).). MS (ESI) m/z 396.2 [M+H]⁺.

Example 32,2-D₂-1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-d₃-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-onep-toluenesulfonate

To a solution of (6bR,10aS)-ethyl3-methyl-d₃-2-oxo-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(9H)-carboxylate solution (1.2 g, 3.77mmol) in THF (7.0 mL) is slowly added BD₃.THF (10 mL, 1M in THF). Theresulting mixture is stirred at room temperature overnight. CD₃OD (1.0mL) is added dropwise to quench the reaction, followed by D₂O (2.0 mL).The solvents are removed under reduced pressure and the residue issuspended in HCl (12 N, 12 mL). The brown suspension is stirred at 95°C. for 24 h and then cooled to 0-5° C. The obtained mixture is adjustedto a pH of ≥14 with NaOH (10 N) and then extracted with dichloromethanethree times (90 mL). The combined organic phase is dried over K₂CO₃,evaporated under reduced pressure, and then dried under vacuum to yield2,2-d₂-(6bR,10aS)-3-methyl-d₃-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline as brown oil (770 mg, 87% yield). MS(ESI) m/z 235.2 [M+H]⁺.

A mixture of 2,2-d₂-(6bR,10aS)-3-methyl-d₃-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline (500 mg 2.13 mmol), KI (720 mg, 4.34mmol), 4-chloro-4′-fluorobutyrophenone (0.7 mL, 4.26 mmol) in DMF (14mL) is bubbled with argon for 10 min. N,N-diisopropylethylamine (0.7 mL,4.02 mmol) is added and the mixture is stirred at 95° C. until all ofthe starting material is consumed. The reaction mixture is cooled toroom temperature and then concentrated under reduced pressure. Theresidue is suspended in dichloromethane (50 mL) and then washed with H₂O(30 mL). The resulting dichloromethane solution is dried over K₂CO₃ andconcentrated to dryness. The residue is purified by silica gel columnchromatography using a gradient of 0-100% ethyl acetate in a mixture ofethyl acetate and methanol (10:1) with 1.5% TEA as eluent to afford2,2-d₂-1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-d₃-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one as a brown oil (446mg, 53% yield). MS (ESI) m/z 399.2 [M+H]⁺.

2,2-D₂-1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-d₃-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one (201 mg, 0.51 mmol)is dissolved in isopropanol (2 mL). To the solution is addedp-toluenesulfonic acid (86.2 mg, 0.45 mmol) in isopropanol (1 mL). Theresulting clear solution is stirred at room temperature until a milkymixture is obtained. The mixture is cooled to 0-5° C. and then filtered.The filter cake is washed with cold isopropanol (2 mL) and then driedunder high vacuum to give the title product as a white solid (180 mg,yield 63%). ¹H NMR (500 MHz, DMSO-d₆) δ 9.1 (s, 1H), 8.0 (ddd, J=2.70,5.52, 8.77 Hz, 2H), 7.5-7.4 (m, 2H), 7.4-7.3 (m, 2H), 7.1 (d, J=7.83 Hz,2H), 6.4 (d, J=7.32 Hz, 1H), 3.6 (s, 1H), 3.5-3.2 (m, 5H), 3.1 (dt,J=7.74, 14.91 Hz, 4H), 2.8-2.5 (m, 1H), 2.3 (s, 4H), 2.2-1.9 (m, 4H).

COMPARATIVE EXAMPLE 41-(4-Fluoro(2,3,5,6-d₄)phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one p-toluenesulfonate

3-Pentanone (4 mL) is added into a mixture of (6bR,10aS)-3-Methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline (460 mg, 2.0 mmol), 2′,3′,5′,6′-d₄-4-chloro-4′-fluorobutyrophenone (428 mg, 2.0 mmol), KI (335 mg,2.0 mmol) and K₂CO₃ (300 mg, 2.2 mmol). The resulting mixture is bubbledwith argon for 10 min and then stirred at 75° C. for 20 h. After thereaction mixture is cooled to room temperature, dichloromethane (30 mL)and H₂O (15 mL) are added. The organic phase is separated and thenextracted with 1N HCl solution (30 mL). The obtained aqueous phase iswashed with dichloromethane (5 mL) and then added slowly to a mixture ofdichloromethane (20 mL) and NaOH (50%, 10 mL) at 0-5° C. After thecompletion of the addition, the organic phase is separated andconcentrated to dryness. The residue is further purified by basic Al₂O₃column chromatography using a gradient of 0-40% ethyl acetate in hexanesas an eluent to give1-(4-fluoro(2,3,5,6-d₄)phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one free base (200 mg,25% yield). MS (ESI) m/z 398.2 [M+H]⁺.

To the purified free base (125 mg, 0.31 mmol) in isopropanol (2 mL) isadded p-toluenesulfonic acid (52 mg, 0.28 mmol) in isopropanol (1 mL) atroom temperature. The resulting clear solution is stirred at roomtemperature until a milky suspension is formed. The solution is cooledto 0-5° C. and then filtered. The filter cake is washed with coldisopropanol (2 mL) and then dried under vacuum to give the titlecompound as a white solid (120 mg, 68% yield). ¹H NMR (500 MHz, DMSO-d₆)δ 9.1 (s, 1H), 7.6-7.4 (m, 2H), 7.1 (d, J=7.82 Hz, 2H), 6.6 (t, J=7.64Hz, 1H), 6.5 (d, J=7.30 Hz, 1H), 6.4 (d, J=7.87 Hz, 1H), 3.6 (dd,J=6.36, 12.51 Hz, 1H), 3.5-3.4 (m, 3H), 3.4-3.3 (m, 2H), 3.3-3.2 (m,1H), 3.2-3.0 (m, 5H), 2.8 (s, 3H), 2.7 (td, J=2.95, 10.27 Hz, 1H),2.7-2.5 (m, 1H), 2.3 (s, 3H), 2.3 (d, J=15.10 Hz, 1H), 2.1-1.9 (m, 3H).

Example 5 Measurement of Parent and Metabolite Levels in Mice

The compounds of Examples 1 to 3 and the compound of Formula Q are dosedin mice, and the levels of the both the parent compounds and the majoramide metabolites are studied. Procedures for the synthesis of thecompound of Formula Q can be found in WO 2008/112280. The compound ofComparative Example 4 is used as an internal standard in each study inorder to control for differences in the inherent rate of metabolism ineach study's animal group. After single dose oral administration of thetest compound and the internal standard, plasma levels of the parentcompounds and metabolites are measured at 0.25, 0.5, 1, 2, 4 and 6hours. The maximum concentration, time to maximum concentration, andArea Under the Curve (AUC) for both the parent and the major amidemetabolite is determined. The AUC value for each test compound isnormalized by taking its ratio to the AUC of the internal standard (Ex.4). Relative Amide Formation is thus calculated as follows for eachExample X (i.e., Ex. 1, Ex. 2, Ex. 3 and Ex. Q):

${{Relative}\mspace{14mu}{Amide}\mspace{14mu}{Formation}\mspace{14mu}\left( {{Ex}.\mspace{11mu} X} \right)} = \frac{{AUC}_{X\text{-}{Parent}}\text{/}{AUC}_{X\text{-}{Amide}}}{{AUC}_{{Std}\text{-}{Parent}}\text{/}{AUC}_{{Std}\text{-}{Amide}}}$The results are summarized in Table 1 below.

Compound Relative Amide Formation Study 1 Ex. 1 0.54 Study 2 Ex. 2 0.38Study 3 Ex. 3 0.31 Study 4 Q 0.79

It is found that the extent of conversion of the parent compound to theamide metabolite is considerably lower for the compounds of Example 1, 2and 3 compared to the non-deuterated compound of Formula Q. Afternormalizing for the extent of metabolism of the internal standard, it isfound that the extent of amide formation for the compounds of Examples1, 2 and 3 is significantly lower than for the non-deuterated compound Q

Receptor binding studies indicate that the compounds of Example 1,Example 2 and Example 3 show substantially the same receptor bindingprofile as the non-deuterated compound of Formula Q (including, e.g.,serotonin receptor (e.g., 5-HT_(2A)), dopamine receptor (e.g., D2) andserotonin transporter binding). For example, the compound of Example 2shows 98% inhibition of the human serotonin 5-HT_(2A) receptor at aconcentration of 0.1 μM.

Example 6 Comparison of Pharmacokinetics Between Deuterated andNon-Deuterated Compounds in Rats

In vivo metabolism (demethylation/oxidation) of the deuterated Compoundof Example 2 (the Compound of Formula I, tosylate salt) is compared tothat of its non-deuterated congener, the Compound of Formula Q (tosylatesalt). The pharmacokinetics of each compound is determined after bothoral (PO) and intravenous (IV) administration in cross-over studies inrats.

PO Administration: Six male Sprague-Dawley rats are divided into two3-rat groups for PO administration of compound on day 1 of the study.Rats in group 1 are administered 10 mg/kg (free base equivalent) of theCompound of Formula Q, while rats in group 2 are administered 10 mg/kg(free base equivalent) of the Compound of Example 2. Blood samples arecollected at 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24-hours post dose andanalyzed for plasma concentration of the administered compound and itsmetabolites. Following a three-day wash out period, the rats of group 1and group 2 are crossed over and administered, respectively, 10 mg/kg(free base equivalent) of the Compound of Example 2 and 10 mg/kg (freebase equivalent) of the Compound of Formula Q. Blood samples arecollected and analyzed as described above, except that an additionalsample is taken pre-dose.

IV Administration: Six male Sprague-Dawley rats are divided into two3-rat groups for IV administration of compound on day 1 of the study.Rats in group 1 are administered 1 mg/kg (free base equivalent) of theCompound of Formula Q, while rats in group 2 are administered 1 mg/kg(free base equivalent) of the Compound of Example 2. Blood samples arecollected at 2 minutes, 5 minutes, 0.25, 0.5, 2, 4, 6, 8 and 12 hourspost dose and analyzed for plasma concentration of the administeredcompound and its metabolites. Following a 72-hour wash out period, therats of group 1 and group 2 are crossed over and administered,respectively, 1 mg/kg (free base equivalent) of the Compound of Example2 and 1 mg/kg (free base equivalent) of the Compound of Formula Q. Bloodsamples are collected and analyzed as described above, except that anadditional sample is taken pre-dose.

All blood samples are processed to plasma and analyzed for parent andmetabolite concentrations using liquid chromatography-tandem massspectrometry (LC-MS/MS). The metabolites analyzed include theN-demethylated amide compound Q-1 (discussed supra). Area under thecurve (AUC) of parent and metabolites based on plasma versus time dataare calculated using Prism 5.04 software (GraphPad Software, Inc.).

The results are summarized in Table 2 below (AUC is shown for 0-24hours, measured in ng-hr/mL):

Test Compound: Formula Q Example 2 (Formula I) PO Parent AUC 56.0 58.5Metabolite Q-1, AUC 128.2 67.8 IV Parent AUC 230.6 257.2 Metabolite Q-1,AUC 6.7 3.7

It is found that after PO dosing of the Compound of Formula Q, theparent compound is extensively metabolized, with extensive formation ofthe N-demethylated/alpha-oxidized amide (Formula Q-1). The AUC of themetabolite Q-1 is 2.2-fold higher than the AUC of the parent. Incontrast, IV dosing resulted in much less extensive metabolism. After IVadministration, the Q-1 metabolite AUC is only about 2% of that of theparent. This demonstrates a high degree of first-pass (hepatic)metabolism that proceeds predominantly by way of N-demethylation andalpha-N oxidation.

In contrast, PO dosing of the Compound of Example 2 results insignificantly less metabolism to the metabolite Q-1 compared to itsnon-deuterated congener. The AUC of the metabolite Q-1 is only 1.2-foldhigher than the AUC of the parent, compared to 2.2-fold higher in thecase of administration of the Compound of Formula Q. Thus, there is a55% decrease in relative metabolism to the demethylated amidederivative. Similar results are obtained for IV administration, whereinthe Q-1 metabolite AUC is found to be about 1% of that of the parent. Itis also shown that when comparing the plasma AUC from equivalent POdosing of the Compound of Formula Q to the Compound of Example 2, thelatter results in approximately half the plasma AUC of metabolite Q-1(67.8 ng-hr/mL vs. 128.2 ng-hr/mL).

Example 7 Comparison of Pharmacokinetics Between Deuterated andNon-Deuterated Compounds in Dogs

In vivo metabolism (demethylation and alpha-oxidation) of the deuteratedCompound of Example 2 (the Compound of Formula I, tosylate salt) iscompared to that of its non-deuterated congener, the Compound of FormulaQ (tosylate salt). The pharmacokinetics of each compound is determinedafter both sublingual (SL) and subcutaneous (SC) administration innon-cross over sequential studies in dogs.

SC Administration: Six male beagle dogs between 2 and 5 years of age arerandomized in two groups of three dogs each. Dogs in group 1 areadministered the compound of Formula Q at a dose of 1 mg/kg (free baseequivalent) in a 0.5% methylcellulose/distilled water vehicle. Dogs ingroup 2 are administered the compound of Example 2 at a dose of 1 mg/kg(free base equivalent) in a 0.5% methylcellulose/distilled watervehicle. Administration is subcutaneous in the intrascapular region viaa 22 or 23 gauge needle. Whole blood samples are collected via the dog'scephalic vein pre-dose, and at post-dose time-points 5, 15 and 30minutes, 1, 2, 4, 6, 8 and 24 hours. Following a minimum 7-day washoutperiod, the dogs are transferred to the sublingual portion of the study.

SL Administration: The dogs of group 1 are administered the compound ofFormula Q at a dose of 1 mg/kg (free base equivalent) in a 0.5%methylcellulose/distilled water vehicle. Dogs in group 2 areadministered the compound of Example 2 at a dose of 1 mg/kg (free baseequivalent) in a 0.5% methylcellulose/distilled water vehicle. Theanimals are anesthetized prior to administration of the dose usingpropofol (6 mg/kg) and anesthesia is maintained for 30 minutes using3-4.5% isoflurane. Administration is sublingual and the dosage isapplied for 30 minutes, then wiped off using unwoven gauze. Whole bloodsamples are collected via the dog's cephalic vein pre-dose, and atpost-dose time-points 5, 15 and 30 minutes, 1, 2, 4, 6, 8, 24, 36 and 48hours.

All blood samples are processed to plasma and analyzed for parent andmetabolite concentrations using liquid chromatography-tandem massspectrometry (LC-MS/MS). The metabolites analyzed include theN-demethylated compound Q-1A (shown below), and theN-demethylated/alpha-oxidized amide compound Q-1 (discussed supra). Areaunder the curve (AUC) of parent and metabolites based on plasma versustime data are calculated using Prism 5.04 software (GraphPad Software,Inc.).

The results are summarized in Table 2 below (AUC is shown for 0-24hours, measured in ng-hr/mL):

Test Compound: Formula Q Example 2 (Formula I) SL Parent AUC 734 1262 Metabolite Q-1A, AUC  23 103 Metabolite Q-1, AUC N.Q. N.D. SC Parent AUC813 785 Metabolite Q-1A, AUC  20  49 Metabolite Q-1, AUC N.D. N.D.

It is found that SL dosing of the compound of Example 2 results in about72% higher parent AUC compared to dosing of the compound of Formula Q.AUC of the des-methyl metabolite Q-1A is about 3% of parent for thecompound of Formula Q, and about 8% of that of the parent for thecompound of Example 2. The concentration of the amide metabolite Q-1 isdetectable at less than 1 ng/mL at each time point for SL administrationof the compound of Formula Q (AUC not quantified), but is undetectablefor SL administration of the compound of Example 2 (<0.1 ng/mL).

In contrast, SC dosing resulted in more comparable results between thetwo compounds. For the compound of Formula Q, the Q-1A metabolite AUC isabout 3% of parent, while for the of the compound of Example 2, the Q-1Ametabolite AUC is about 6% of parent. For SC dosing, the metabolite Q-1was undetectable (<0.1 ng/mL) for both compounds. The AUC of parent isfound to be comparable between the deuterated and non-deuteratedcompounds.

Comparing the SC to SL results, for the compound of Formula Q, SLadministration resulted in 10% less net AUC of parent compound comparedto SC administration. In contrast, dosing the deuterated compound ofExample 2 leads to 61% higher parent AUC for SL compared to SC. Withoutbeing bound by theory, it is believed that this difference is related todifferences in the rate of absorption from the subcutaneous spacebetween the deuterated and non-deuterated species.

Taken together, these results show that deuteration of the methylenegroup adjacent to the piperazine nitrogen reduced metabolism of thecompound of the invention compared to its non-deuterated analog,resulting in higher and more prolonged plasma concentrations of theparent drug. Since the concentration of the de-methylated Q-1Ametabolite is found to be higher for the deuterated compound, comparedto the non-deuterated compound, the results suggest, as seen in rats,that deuteration is inhibiting the subsequent oxidation of thede-methylated amine to its amide derivative (Q-1).

The formation of the metabolite Q-1 is believed to occur by way of theintermediate metabolite Q-1A, shown below:

Thus, the parent compound Q undergoes de-methylation to an aminefollowed by oxidation of the methylene adjacent to the amine to form theamide metabolite, Q-1A. The results presented in Examples 6 and 7demonstrate that for both dogs and rats, deuteration of the Compound ofFormula Q at the indicated position, to yield the Compound of Example 2,significantly decreases oxidation of the N-methyl piperazine moiety,thus indicating blockage of this metabolic pathway.

The reduction in metabolism of the parent compound Q to the Q-1metabolite can have important clinical consequences, because the parentcompound Q, the Q-1 metabolite and the Q-1A metabolites are all known tobe pharmacologically active species, but with different receptorselectivity profiles. For example, Table 2 summarizes some of thereceptor activity distinctions between these species (measurements areKi (nM)):

Receptor Cmpd. Q Cmpd. Q-1A Cmpd. Q-1 Serotonin 5-HT_(2A) 0.54 2 11Dopamine D2 32 30 50-250 Dopamine D1 52 110 22 Serotonin Transporter33-72 31-78 >600 Table 2 shows that while all three compounds activity at the serotonin,dopamine D1, dopamine D₂ and serotonin transporter receptors, theirrelative activities at these receptors varies. While the metabolite Q-1Ahas a largely similar pharmacologic profile to the parent Q, Table 2shows that the metabolite Q-1 diverges significantly in that there ismuch less relative activity at the Dopamine D₂ receptor and at theserotonin transporter. In addition, the compound of formula Q-1, unlikeQ and Q-1A, has been found to be a potent mu opiate receptor antagonist(Ki of about 22 nM). Because of their different receptor activityprofiles, each of the relevant metabolites has distinct functionalpharmacological effects compared to the parent drug Q. Thus, by blockingthe metabolism pathway which converts the compounds Q and Q-1A to themetabolite Q-1, a significant effect on pharmacological function canresult. The present invention is therefore useful in inhibiting thismetabolic pathway in order to modulate overall pharmacological profileprovided by the parent drugs.

The invention claimed is:
 1. A compound of formula I,

in free or salt form; or a compound of formula II,

in free or salt form; or a compound of formula III,

in free or salt form.
 2. The compound according to claim 1, wherein saidcompound is in salt form.
 3. The compound according to claim 2, whereinthe salt is a toluenesulfonic acid addition salt.
 4. The compoundaccording to claim 1, wherein the compound is the compound of Formula IIin free or salt form.
 5. A pharmaceutical composition comprising acompound according to claim 1, in free or pharmaceutically acceptablesalt form, in combination or association with a pharmaceuticallyacceptable diluent or carrier.
 6. A method for the treatment of acentral nervous system disorder comprising administering to a patient inneed thereof a therapeutically effective amount of the compoundaccording to claim 1, in free or pharmaceutically acceptable salt form,wherein said disorder is selected from obesity, anxiety, depression,refractory depression, major depressive disorder (MDD), psychosis,schizophrenia, sleep disorders, sexual disorders, migraine, socialphobias, agitation, agitation in dementia, agitation in autism,post-traumatic stress disorder, impulse control disorders, andintermittent explosive disorder; disorders associated with dementiaselected from the group consisting of agitation/irritation,aggressive/assaultive behavior, anger, physical or emotional outbursts,psychosis, depression, and sleep disorders; delusional disorder, majordepression with psychosis, bipolar disorder with psychotic symptoms,brief psychotic disorder, schizophreniform disorder, schizoaffectivedisorder, and psychosis caused by a medical condition or substance use.7. The method according to claim 6, wherein said disorder is selectedfrom a group consisting of obesity, anxiety, depression, refractorydepression, major depressive disorder (MDD), psychosis, schizophrenia,sleep disorders, sexual disorders, migraine, social phobias, agitation,agitation in dementia, agitation in autism, post-traumatic stressdisorder, impulse control disorders, and intermittent explosivedisorder.
 8. The method according to claim 6, wherein said disorder isone or more disorders associated with dementia selected from the groupconsisting of agitation/irritation, aggressive/assaultive behavior,anger, physical or emotional outbursts, psychosis, depression, and sleepdisorders.
 9. The method according to claim 6, wherein the centralnervous system disorder is residual phase symptoms of psychosis selectedfrom blunted affect, emotional withdrawal, poor rapport, passive orapathetic social withdrawal, difficulty in abstract thinking, lack ofspontaneity and flow of conversation, stereotyped thinking; somaticconcern, anxiety, guilt feelings, tension, mannerisms and posturing,depression, motor retardation, uncooperativeness, unusual thoughtcontent, disorientation, poor attention, lack of judgment and insight,disturbance of volition, poor impulse control, preoccupation and activesocial avoidance; cognitive impairment, and sleep disorders.
 10. Themethod according to claim 6, further comprising the administration ofone or more other therapeutic agents.
 11. The method according to claim10, wherein the one or more other therapeutic agents are selected fromcompounds that modulate GABA activity, a GABA-B agonist, a 5-HTmodulator, a melatonin agonist, an ion channel modulator, a serotonin-2antagonist/reuptake inhibitor (SARIs), a 5-HT₆ antagonist, an orexinreceptor antagonist, an H3 agonist, a noradrenergic antagonist, agalanin agonist, a CRH antagonist, human growth hormone, a growthhormone agonist, estrogen, an estrogen agonist, a neurokinin-1 drug; andantipsychotic agents; in free or pharmaceutically acceptable salt form.12. The method according to claim 10, wherein the one or more othertherapeutic agents are antipsychotic agents selected fromchlorpromazine, haloperidol, droperidol, fluphenazine, loxapine,mesoridazine molindone, perphenazine, pimozide, prochlorperazinepromazine, thioridazine, thiothixene, trifluoperazine, clozapine,aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone,paliperidone, asenapine, lurasidone, iloperidone, cariprazine,amisulpride, zotepine, sertindole, in free or pharmaceuticallyacceptable salt form.
 13. The method according to claim 10, wherein theone or more other therapeutic agents are anti-depressive agents selectedfrom one or more of amitriptyline, amoxapine, bupropion, citalopram,clomipramine, desipramine, doxepin, duloxetine, escitalopram,fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline,mirtazapine, nefazodone, nortriptyline, paroxetine, phenelazine sulfate,protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, andvenlafaxine.
 14. The method according to claim 10, wherein the one ormore other therapeutic agents are anti-depressive agent selected fromselective serotonin reuptake inhibitors (SSRIs),serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclicantidepressants.
 15. The method according to claim 14, wherein theanti-depressive agent is an SSRI.
 16. The method according to claim 8,wherein said dementia is selected from mild cognition impairment, seniledementia, Alzheimer's disease, Pick's disease, fronto-temporal dementia,parasupranuclear palsy, dementia with Lewy bodies, vascular dementia,Huntington's disease, Parkinson's disease, multiple sclerosis,amyotrophic lateral sclerosis, elderly depression, Wernicke-Korsakoffssyndrome, cortico-basal degenerations and prion disease, autism, orattention deficit hyperactivity disorder.
 17. The method according toclaim 6, wherein the central nervous system disorder is residual phasesymptoms of schizophrenia, delusional disorder, major depression withpsychosis, bipolar disorder with psychotic symptoms, brief psychoticdisorder, schizophreniform disorder, schizoaffective disorder orpsychosis caused by a medical condition or substance use; wherein theresidual phase symptoms are selected from blunted affect, emotionalwithdrawal, poor rapport, passive or apathetic social withdrawal,difficulty in abstract thinking, lack of spontaneity and flow ofconversation, stereotyped thinking; somatic concern, anxiety, guiltfeelings, tension, mannerisms and posturing, depression, motorretardation, uncooperativeness, unusual thought content, disorientation,poor attention, lack of judgment and insight, disturbance of volition,poor impulse control, preoccupation and active social avoidance;cognitive impairment, and sleep disorders.
 18. The method according toclaim 17, wherein the central nervous system disorder is residualsymptoms of schizophrenia.
 19. The compound according to claim 1,wherein the compound has greater than 90% incorporation of deuterium atthe indicated deuterium positions of the structure.
 20. The compoundaccording to claim 1, wherein the compound has greater than 97%incorporation of deuterium, at the indicated deuterium positions of thestructure.
 21. The composition according to claim 5, wherein thecompound is the compound of Formula II.
 22. The compound according toclaim 3, wherein the compound is the compound of Formula II.
 23. Thecompound according to claim 20, wherein the compound is the compound ofFormula II.